Substituted bicyclic derivatives for the treatment of abnormal cell growth

ABSTRACT

The invention relates to compounds of the formula 1 
                 
 
and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein R 1 , R 3 , R 4 , R 5 , R 11 , m and p are as defined herein. The invention also relates to methods of treating abnormal cell growth in mammals by administering the compounds of formula 1 and to pharmaceutical compositions for treating such disorders which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.

This U.S. patent application claims priority from and the benefit ofU.S. Provisional Patent Application No. 60/213,136, filed Jun. 20, 2000.

BACKGROUND OF THE INVENTION

This invention relates to novel bicyclic derivatives that are useful inthe treatment of abnormal cell growth, such as cancer, in mammals. Thisinvention also relates to a method of using such compounds in thetreatment of abnormal cell growth in mammals, especially humans, and topharmaceutical compositions containing such compounds.

It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e., a genewhich, on activation, leads to the formation of malignant tumor cells).Many oncogenes encode proteins that are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype.

Receptor tyrosine kinases are enzymes which span the cell membrane andpossess an extracellular binding domain for growth factors such asepidermal growth factor, a transmembrane domain, and an intracellularportion which functions as a kinase to phosphorylate specific tyrosineresidues in proteins and hence to influence cell proliferation. Otherreceptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr,and VEGFR. It is known that such kinases are frequently aberrantlyexpressed in common human cancers such as breast cancer,gastrointestinal cancer such as colon, rectal or stomach cancer,leukemia, and ovarian, bronchial or pancreatic cancer. It has also beenshown that epidermal growth factor receptor (EGFR), which possessestyrosine kinase activity, is mutated and/or overexpressed in many humancancers such as brain, lung, squamous cell, bladder, gastric, breast,head and neck, oesophageal, gynecological and thyroid tumors.

Accordingly, it has been recognized that inhibitors of receptor tyrosinekinases are useful as selective inhibitors of the growth of mammaliancancer cells. For example, erbstatin, a tyrosine kinase inhibitor,selectively attenuates the growth in athymic nude mice of a transplantedhuman mammary carcinoma which expresses epidermal growth factor receptortyrosine kinase (EGFR) but is without effect on the growth of anothercarcinoma which does not express the EGF receptor. Thus, the compoundsof the present invention, which are selective inhibitors of certainreceptor tyrosine kinases, are useful in the treatment of abnormal cellgrowth, in particular cancer, in mammals. In addition to receptortyrosine kianses, the compounds of the present invention can alsodisplay inhibitory activity against a variety of other non-receptortyrosine kinases (eg: Ick, src, abl) or serine/threonine kinases (e.g.:cyclin dependent kinases).

Various other compounds, such as styrene derivatives, have also beenshown to possess tyrosine kinase inhibitory properties. More recently,five European patent publications, namely EP 0 566 226 A1 (publishedOct. 20, 1993), EP 0 602 851 A1 (published Jun. 22, 1994), EP 0 635 507Al (published Jan. 25, 1995), EP 0 635 498 A1 (published Jan. 25, 1995),and EP 0 520 722 A1 (published Dec. 30, 1992), refer to certain bicyclicderivatives, in particular quinazoline derivatives, as possessinganti-cancer properties that result from their tyrosine kinase inhibitoryproperties. Also, World Patent Application WO 92/20642 (published Nov.26, 1992), refers to certain bis-mono and bicyclic aryl and heteroarylcompounds as tyrosine kinase inhibitors that are useful in inhibitingabnormal cell proliferation. World Patent Applications WO96/16960(published Jun. 6, 1996), WO 96/09294 (published Mar. 6, 1996), WO97/30034 (published Aug. 21, 1997), WO 98/02434 (published Jan. 22,1998), WO 98/02437 (published Jan. 22, 1998), and WO 98/02438 (publishedJan. 22, 1998), also refer to substituted bicyclic heteroaromaticderivatives as tyrosine kinase inhibitors that are useful for the samepurpose. Other patent applications that refer to anti-cancer compoundsare U.S. patent application Ser. No. 09/488,350 (filed Jan. 20, 2000)and Ser. No. 09/488,378 (filed Jan. 20, 2000), both of which areincorporated herein by reference in their entirety.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula 1

and to pharmaceutically acceptable salts, solvates and prodrugs thereof,wherein:

m is an integer from 0 to 3;

p is an integer from 0 to 4;

each R¹ and R² is independently selected from H and C₁-C₆ alkyl;

R³ is —(CR¹R²)_(t)(4 to 10 membered heterocyclic), wherein t is aninteger from 0 to 5, said heterocyclic group is optionally fused to abenzene ring or a C₅-C₈ cycloalkyl group, the —(CR¹R²)_(t)— moiety ofthe foregoing R³ group optionally includes a carbon-carbon double ortriple bond where t is an integer between 2 and 5, and the foregoing R³groups, including any optional fused rings referred to above, areoptionally substituted by 1 to 5 R⁸ groups;

R⁴ is —(CR¹⁶R¹⁷)_(m)—C≡C—(CR¹⁶R¹⁷)_(t)R⁹,—(CR¹⁶C¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(t)—R⁹,—(CR¹⁶R¹⁷)_(m)—C≡C—(CR¹⁶R¹⁷)_(k)R¹³,—(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(k)R¹³, or —(CR¹⁶R¹⁷)_(t)R⁹, wherein theattachment point to R⁹ is through a carbon atom of the R⁹ group, each kis an integer from 1 to 3, each t is an integer from 0 to 5, and each mis an integer from 0 to 3;

each R⁵ is independently selected from halo, hydroxy, —NR¹R², C₁-C₆alkyl, trifluoromethyl, C₁-C₆ alkoxy, trifluoromethoxy, —NR⁶C(O)R¹,—C(O)NR⁶R⁷, —SO₂NR⁶R⁷, —NR⁶C(O)NR⁷R¹, and —NR⁶C(O)OR⁷;

each R⁶, R^(6a) and R⁷ is independently selected from H, C₁-C₆ alkyl,—(CR¹R²)_(t)(C₆-C₁₀ aryl), and —(CR¹R²)_(t)(4 to 10 memberedheterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbonatoms of the heterocyclic group are optionally substituted with an oxo(═O) moiety, the alkyl, aryl and heterocyclic moieties of the foregoingR⁶ and R⁷ groups are optionally substituted with 1 to 3 substituentsindependently selected from halo, cyano, nitro, —NR¹R², trifluoromethyl,trifluoromethoxy, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxy,and C₁-C₆ alkoxy;

or R⁶ and R⁷, or R^(6a) and R⁷, when attached to a nitrogen atom(including the same nitrogen atom or two separate nitrogen atoms inproximity to each other through interconection by, for instance, —C(O)or —SO₂—), can be taken together to form a 4 to 10 membered heterocyclicring which may include 1 to 3 additional hetero moieties, in addition tothe nitrogen to which said R⁶, R^(6a), and R⁷ are attached, selectedfrom N,N(R¹), O, and S, provided two O atoms, two S atoms or an O and Satom are not attached directly to each other;

each R⁸ is independently selected from oxo (═O), halo, cyano, nitro,trifluoromethoxy, trifluoromethyl, azido, hydroxy, C₁-C₆ alkoxy, C₁-C₁₀alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,—NR⁶C(O)R⁷, —NR⁶SO₂NR⁷R¹, —NR⁶C(O)NR¹R⁷, —NR⁶C(O)OR⁷, —C(O)NR⁶R⁷,—NR⁶R⁷, —NR⁶CR⁷, —SO₂NR⁶R⁷, —S(O)_(j)(C₁-C₆ alkyl) wherein j is aninteger from 0 to 2, —(CR¹R²)t(C₆-C₁₀ aryl), —(CR¹R²)_(t)(4 to 10membered heterocyclic), —(CR¹R²)_(q)C(O)(CR¹R²)_(t)(C₆-C₁₀ aryl),—(CR¹R²)_(q)C(O)(CR¹R²)_(t)(4 to 10 membered heterocyclic),—(CR¹R²)_(t)O(CR¹R²)_(q)(C₆-C₁₀ aryl), —(CR¹R²)_(t)O(CR¹R²)_(q)(4 to 10membered heterocyclic), —(CR¹R²)_(q)S(O)_(j)(CR¹R²)_(t)(C₆-C₁₀ aryl),and —(CR¹R²)_(q)S(O)_(j)(CR¹R²)_(t)(4 to 10 membered heterocyclic),wherein j is 0, 1 or 2, q and t are each independently an integer from 0to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of theforegoing R⁸ groups are optionally substituted with an oxo (═O) moiety,and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of theforegoing R⁸ groups are optionally substituted with 1 to 3 substituentsindependently selected from halo, cyano, nitro, trifluoromethyl,trifluoromethoxy, azido, —OR⁶, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷,—C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—(CR¹R²)_(t)(C₆-C₁₀ aryl), and —(CR¹R²)_(t)(4 to 10 memberedheterocyclic), wherein t is an integer from 0 to 5;

R⁹ is a non-aromatic mono-cyclic ring, a fused or bridged bicyclic ring,or a spirocyclic ring, wherein said ring contains from 3 to 12 carbonatoms in which from 0 to 3 carbon atoms are optionally replaced with ahetero moiety independently selected from N, O, S(O), wherein j is aninteger from 0 to 2, and —NR¹—, provided that two O atoms, two S(O)_(j)moieties, an O atom and a S(O)_(j) moiety, an N atom and an S atom, oran N atom and an O atom are not attached directly to each other withinsaid ring, and wherein the carbon atoms of said ring are optionallysubstituted with 1 or 2 R⁸ groups;

each R¹¹ is independently selected from the substituents provided in thedefinition of R⁸, except R¹¹ is not oxo(═O);

R¹² is R⁶, —OR⁶, —OC(O)R⁶, —OC(O)NR⁶R⁷, —OCO₂R⁶, —S(O)_(j)R⁶,—S(O),NR⁶R⁷, —NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶SO₂R⁷, —NR⁶C(O)NR^(6a)R⁷,—NR⁶SO₂NR^(6a)R⁷, —NR⁶CO₂R⁷, CN, —C(O)R⁶, or halo, wherein j is aninteger from 0 to 2;

R¹³ is —NR¹R¹⁴ or —OR¹⁴;

R¹⁴ is H, R¹⁵, —C(O)R¹⁵, —SO₂R¹⁵, —C(O)NR¹⁵R⁷, —SO₂NR¹⁵R⁷, or —CO₂R¹⁵;

R¹⁵ is R¹⁸, —(CR¹R²)_(t)(C₆-C₁₀, aryl), —(CR¹R²)_(t)(4 to 10 memberedheterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbonatoms of the heterocyclic group are optionally substituted with an oxo(═O) moiety, and the aryl and heterocyclic moieties of the foregoing R¹⁵groups are optionally substituted with 1 to 3 R⁸ substituents;

each R¹⁶ and R¹⁷ is independently selected from H, C₁-C₆ alkyl, and—CH₂OH, or R¹⁶ and R¹⁷ are taken together as —CH₂CH₂— or —CH₂CH₂CH₂—;

R¹⁸ is C₁-C₆ alkyl wherein each carbon not bound to a N or O atom, or toS(O)_(j), wherein j is an integer from 0 to 2, is optionally substitutedwith R¹²;

and wherein any of the above-mentioned substituents comprising a CH₃(methyl), CH₂ (methylene), or CH (methine) group, which is not attachedto a halogeno, SO or SO₂ group or to a N, O or S atom, is optionallysubsituted with a group selected from hydroxy, halo, C₁-C₄ alkyl, C₁-C₄alkoxy and —NR¹R².

In a specific embodiment of the present invention, R³ is —(CR¹R²)_(t)(4to 10 membered heterocyclic), wherein t is an integer from 0 to 5; saidheterocyclic group is optionally fused to a benzene ring or a C₅-C₈cycloalkyl group, and the foregoing R³ groups, including any optionalfused rings referred to above, are optionally substituted by 1 to 3 R⁸groups.

Other specific embodiments of the compounds of formula 1 include thosewherein R³ is —(CR¹R²)_(t)(4 to 10 membered heterocyclic), wherein t isan integer from 0 to 5, and the foregoing R³ groups are optionallysubstituted by 1 to 3 R⁸ groups.

Other specific embodiments of the compounds of formula 1 include thosewherein R³ is selected from

wherein the foregoing R³ groups are optionally substituted by 1 to 3 R⁸groups.

Other specific embodiments of the compounds of formula 1 include thosewherein R³ is pyridin-3-yl optionally substituted by 1 to 3 R⁸ groups.

Other specific embodiments of the compounds of formula 1 include thosewherein the following structural portion of the compound of formula 1

is selected from the group consisting of

3-Methyl-4-(pyridin-2-yloxy)-phenylamino

3-Chloro-4-(pyridin-2-yloxy)-phenylamino

3-Methoxy-4-(pyridin-2-yloxy)-phenylamino

4-(pyridin-2-yloxy)-phenylamino

2-Methyl-4-(pyridin-2-yloxy)-phenylamino

2-Methoxy-4-(pyridin-2-yloxy)-phenylamine

3-Chloro-4-(6-methyl-pyridin-2-yloxy)-phenylamino

3-Methoxy-4-(6-methyl-pyridin-2-yloxy)-phenylamino

3-Methyl-4-(6-methyl-pyridin-2-yloxy)-phenylamino

2-Methoxy-4-(6-methyl-pyridin-2-yloxy)-phenylamino

2-Methyl-4-(6-methyl-pyridin-2-yloxy)-phenylamino

4-(6-methyl-pyridin-2-yloxy)-phenylamino

3-Methoxy-4-(2-methyl-pyridin-3-yloxy)-phenylamino

3-Methyl-4-(2-methyl-pyridin-3-yloxy)-phenylamino

3-Chloro-4-(2-methyl-pyridin-3-yloxy)-phenylamino

2-Methoxy-4-(2-methyl-pyridin-3-yloxy)-phenylamino

2-Methyl-4-(2-methyl-pyridin-3-yloxy)-phenylamino

4-(2-methyl-pyridin-3-yloxy)-phenylamino

3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino

3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino

3-Methoxy-4-(6-methyl-pyridin-3-yloxy)-phenylamino

2-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino

2-Methoxy-4-(6-methyl-pyridin-3-yloxy)-phenylamino

4-(6-methyl-pyridin-3-yloxy)-phenylamino

3-Methyl-4-(pyridin-3-yloxy)-phenylamino

3-Chloro-4-(pyridin-3-yloxy)-phenylamino

3-Methoxy-4-(pyridin-3-yloxy)-phenylamino

2-Methyl-4-(pyridin-3-yloxy)-phenylamino

2-Methoxy-4-(pyridin-3-yloxy)-phenylamino

4-(pyridin-3-yloxy)-phenylamino

3-Methyl-4-(2-methyl-pyrimidin-5-yloxy)-phenylamino

3-Chloro-4-(2-methyl-pyrimidin-5-yloxy)-phenylamino

3-Methoxy-4-(2-methyl-pyrimidin-5-yloxy)-phenylamino

2-Methyl-4-(2-methyl-pyrimidin-5-yloxy)-phenylamino

2-Methoxy-4-(2-methyl-pyrimidin-5-yloxy)-phenylamino

4-(2-methyl-pyrimidin-5-yloxy)-phenylamino

3-Methyl-4-(4-methyl-pyrimidin-5-yloxy)-phenylamino

3-Chloro-4-(4-methyl-pyrimidin-5-yloxy)-phenylamino

3-Methoxy-4-(4-methyl-pyrimidin-5-yloxy)-phenylamino

2-Methyl4-(4-methyl-pyrimidin-5-yloxy)-phenylamino

2-Methoxy-4-(4-methyl-pyrimidin-5-yloxy)-phenylamino

4-(4-methyl-pyrimidin-5-yloxy)-phenylamino

3-Methyl-4-(2-methyl-pyridin-4-yloxy)-phenylamino

3-Chloro-4-(2-methyl-pyridin-4-yloxy)-phenylamino

3-Methoxy-4-(2-methyl-pyridin-4-yloxy)-phenylamino

2-Methyl-4-(2-methyl-pyridin-4-yloxy)-phenylamino

2-Methoxy-4-(2-methyl-pyridin-4-yloxy)-phenylamino

4-(2-methyl-pyridin-4-yloxy)-phenylamino

3-Methyl-4-(pyridin-4-yloxy)-phenylamino

3-Chloro-4-(pyridin-4-yloxy)-phenylamino

3-Methoxy-4-(pyridin-4-yloxy)-phenylamino

2-Methyl-4-(pyridin-4-yloxy)-phenylamino

2-Methoxy-4-(pyridin-4-yloxy)-phenylamino

4-(pyridin-4-yloxy)-phenylamino

3-Methyl-4-(2-methyl-pyrimidin-4-yloxy)-phenylamino

3-Methoxy-4-(2-methyl-pyrimidin-4-yloxy)-phenylamino

3-Chloro-4-(2-methyl-pyrimidin-4-yloxy)-phenylamino

2-Methyl-4-(2-methyl-pyrimidin-4-yloxy)-phenylamino

2-Methoxy-4-(2-methyl-pyrimidin-4-yloxy)-phenylamino

4-(2-methyl-pyrimidin-4-yloxy)-phenylamino

3-Methyl-4-(6-methyl-pyrimidin-4-yloxy)-phenylamino

3-Methoxy-4-(6-methyl-pyrimidin-4-yloxy)-phenylamino

3-Chloro-4-(6-methyl-pyrimidin-4-yloxy)-phenylamino

2-Methyl4-(6-methyl-pyrimidin-4-yloxy)-phenylamino

2-Methoxy-4-(6-methyl-pyrimidin-4-yloxy)-phenylamino

4-(6-methyl-pyrimidin-4-yloxy)-phenylamino

3-Methyl-4-(pyrazin-2-yloxy)-phenylamino

3-Methoxy-4-(pyrazin-2-yloxy)-phenylamino

3-Chloro-4-(pyrazin-2-yloxy)-phenylamino

2-Methyl-4-(pyrazin-2-yloxy)-phenylamino

2-Methoxy-4-(pyrazin-2-yloxy)-phenylamino

4-(pyrazin-2-yloxy)-phenyl amino

3-Chloro-4-(3-methyl-pyrazin-2-yloxy)-phenylamino

3-Methoxy-4-(3-methyl-pyrazin-2-yloxy)-phenylamino

3-Methyl-4-(3-methyl-pyrazin-2-yloxy)-phenylamino

2-Methoxy-4-(3-methyl-pyrazin-2-yloxy)-phenylamino

2-Methyl-4-(3-methyl-pyrazin-2-yloxy)-phenylamino

4-(3-methyl-pyrazin-2-yloxy)-phenylamino

3-Chloro-4-(5-methyl-pyrazin-2-yloxy)-phenylamino

3-Methoxy-4-(5-methyl-pyrazin-2-yloxy)-phenylamino

3-Methyl-4-(5-methyl-pyrazin-2-yloxy)-phenylamino

2-Methoxy-4-(5-methyl-pyrazin-2-yloxy)-phenylamino

2-Methyl-4-(5-methyl-pyrazin-2-yloxy)-phenylamino

4-(5-methyl-pyrazin-2-yloxy)-phenylamino

3-Chloro-4-(6-methyl-pyrazin-2-yloxy)-phenylamino

3-Methoxy-4-(6-methyl-pyrazin-2-yloxy)-phenylamino

3-Methyl-4-(6-methyl-pyrazin-2-yloxy)-phenylamino

2-Methoxy-4-(6-methyl-pyrazin-2-yloxy)-phenylamino

2-Methyl-4-(6-methyl-pyrazin-2-yloxy)-phenylamino

4-(6-methyl-pyrazin-2-yloxy)-phenylamino

3-Methyl-4-(pyridazin-3-yloxy)-phenylamino

3-Chloro-4-(pyridazin-3-yloxy)-phenylamino

3-Methoxy-4-(pyridazin-3-yloxy)-phenylamino

2-Methyl-4-(pyridazin-3-yloxy)-phenylamino

2-Methoxy-4-(pyridazin-3-yloxy)-phenylamino

4-(pyridazin-3-yloxy)-phenylamino

3-Methyl-4-(6-methyl-pyridazin-3-yloxy)-phenylamino

3-Chloro-4-(6-methyl-pyridazin-3-yloxy)-phenylamino

3-Methoxy-4-(6-methyl-pyridazin-3-yloxy)-phenylamino

2-Methyl-4-(6-methyl-pyridazin-3-yloxy)-phenylamino

2-Methoxy-4-(6-methyl-pyridazin-3-yoxy)-phenylamino

4-(6-methyl-pyridazin-3-yloxy)-phenylamino

3-Methyl-4-(6-methyl-pyridazin-4-yloxy)-phenylamino

3-Chloro-4-(6-methyl-pyridazin-4-yloxy)-phenylamino

3-Methoxy-4-(6-methyl-pyridazin-4-yloxy)-phenylamino

2-Methyl-4-(6-methyl-pyridazin-4-yloxy)-phenylamino

2-Methoxy-4-(6-methyl-pyridazin-4-yloxy)-phenylamino

4-(6-methyl-pyridazin-4-yloxy)-phenylamino

3-Methyl-4-(3-methyl-pyridazin-4-yloxy)-phenylamino

3-Chloro-4-(3-methyl-pyridazin-4-yloxy)-phenylamino

3-Methoxy-4-(3-methyl-pyridazin-4-yloxy)-phenylamino

2-Methyl-4-(3-methyl-pyridazin-4-yloxy)-phenylamino

2-Methoxy-4-(3-methyl-pyridazin-4-yloxy)-phenylamino

4-(3-methyl-pyridazin-4-yloxy)-phenylamino

3-Methyl-4-(pyridazin-4-yloxy)-phenylamino

3-Chloro-4-(pyridazin-4-yloxy)-phenylamino

3-Methoxy-4-(pyridazin-4-yloxy)-phenylamino

2-Methyl-4-(pyridazin-4-yloxy)-phenylamino

2-Methoxy-4-(pyridazin-4-yloxy)-phenylamino

4-(pyridazin-4-yloxy)-phenylamino

3-Chloro-4-(1-methyl-1H-pyrazol-4-yloxy)-phenylamino

3-Methoxy-4-(1-methyl-1H-pyrazol-4-yloxy)-phenylamino

3-Methyl-4-(1-methyl-1H-pyrazol-4-yloxy)-phenylamino

2-Methoxy-4-(1-methyl-1H-pyrazol-4-yloxy)-phenylamino

2-Methyl-4-(1-methyl-1H-pyrazol-4-yloxy)-phenylamino, and

4-(1-methyl-1H-pyrazol-4-yloxy)-phenylamino.

Other specific embodiments of the compounds for formula 1 include thosewherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C≡C—(CR¹⁶R¹⁷)_(t)R⁹, wherein m is aninteger from 0 to 3, and t is an integer from 0 to 5.

Other specific embodiments of the compounds for formula 1 include thosewherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C≡C—(CR¹⁶R¹⁷)_(t)R⁹, wherein m is aninteger from 0 to 3, and t is an integer from 0 to 5, wherein R⁹ isselected from 3-piperidinyl and 4-piperidinyl each of which isoptionally substituted with 1 or 2 R⁸ groups.

Other specific embodiments of the compounds for formula 1 include thosewherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(t)—R⁹, wherein m is aninteger from 0 to 3, and t is an integer from 0 to 5.

Other specific embodiments of the compounds for formula 1 include thosewherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(t)—R⁹, wherein m is aninteger from 0 to 3, and t is an integer from 0 to 5, wherein R⁹ isselected from 3-piperidinyl and 4-piperidinyl (optionally substitutedwith 1 or 2 R⁸ groups).

Other specific embodiments of the compounds for formula 1 include thosewherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(t)—R¹³, wherein k is aninteger from 1 to 3 and m is an integer from 0 to 3.

Other specific embodiments of the compounds for formula 1 include thosewherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C≡C—(CR¹⁶R¹⁷)_(k)R¹³, wherein k is aninteger from 1 to 3 and m is an integer from 0 to 3, wherein R¹³ is—NR¹R¹⁴, wherein R¹⁴ is selected from —C(O)R¹⁵, —SO₂R¹⁵, and C(O)NR¹⁵R⁷.

Other specific embodiments of the compounds for formula 1 include thosewherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C≡C—(CR¹⁶R¹⁷)_(k)R¹³, wherein k is aninteger from 1 to 3 and m is an integer from 0 to 3.

Other specific embodiments of the compounds for formula 1 include thosewherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(k)R¹³, wherein k is aninteger from 1 to 3 and m is an integer from 0 to 3, wherein R¹³ is—NR¹R¹⁴, wherein R¹⁴ is selected from —C(O)R¹⁵, —SO₂R¹⁵, and C(O)NR¹⁵R⁷.

Other specific embodiments of the compounds for formula 1 include thosewherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(k)R¹³ or—(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(k)R¹³, wherein k is an integer from 1 to 3and m is an integer from 0 to 3, R¹³ is —NR¹R¹⁴ or —OR¹⁴, R¹⁴ is R¹⁵,R¹⁵ is R¹⁸, and R¹⁸ is C₁-C₆ alkyl optionally substituted by —OR⁶,—S(O)_(j)R⁶, —NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶SO₂R⁷, —NR⁶CO₂R⁷, CN, —C(O)R⁶, orhalo.

Specific preferred compounds of the present invention include thoseselected from the group consisting of:

(+)-[3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;

2-Methoxy-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide

(+)-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;

2-Methoxy-N-(3-{4-[3-methyl-4-(2-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide

[3-Methyl-4-(2-methyl-pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine

[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;

2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide;

2-Fluoro-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide;

E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide;

[3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;

2-Methoxy-N-(1-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylethynyl}-cyclopropyl)-acetamide;

E-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-2-methoxy-acetamide;

N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide;

N-(3-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide;

E-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide;

E-2-Ethoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide;

1-Ethyl-3-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea;

Piperazine-1-carboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide;

(+)-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide;

2-Dimethylamino-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide;

E-N-(3-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-methanesulfonamide;

Isoxazole-5-carboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide;

1-(1,1-Dimethyl-3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-3-ethyl-urea;

and the pharmaceutically acceptable salts, prodrugs and solvates of theforegoing compounds.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, solvate or prodrug thereof, thatis effective in treating abnormal cell growth. In one embodiment of thismethod, the abnormal cell growth is cancer, including, but not limitedto, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer, rectal cancer, cancer of the anal region, stomachcancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said method, said abnormal cell growth is a benignproliferative disease, including, but not limited to, psoriasis, benignprostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of formula 1, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, that is effective in treating abnormalcell growth in combination with an anti-tumor agent selected from thegroup consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

This invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, solvate or prodrug thereof, thatis effective in treating abnormal cell growth, and a pharmaceuticallyacceptable carrier. In one embodiment of said composition, said abnormalcell growth is cancer, including, but not limited to, lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said pharmaceutical composition, said abnormal cell growthis a benign proliferative disease, including, but not limited to,psoriasis, benign prostatic hypertrophy or restinosis.

The invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human, whichcomprises an amount of a compound of formula 1, as defined above, or apharmaceutically acceptable salt, solvate or prodrug thereof, that iseffective in treating abnormal cell growth in combination with apharmaceutically acceptable carrier and an anti-tumor agent selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, and anti-androgens.

This invention also relates to a method for the treatment of a disorderassociated with angiogenesis in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula 1,as defined above, or a pharmaceutically acceptable salt, solvate orprodrug thereof, that is effective in treating said disorder. Suchdisorders include cancerous tumors such as melanoma; ocular disorderssuch as age-related macular degeneration, presumed ocular histoplasmosissyndrome, and retinal neovascularization from proliferative diabeticretinopathy; rheumatoid arthritis; bone loss disorders such asosteoporosis, Paget's disease, humoral hypercalcemia of malignancy,hypercalcemia from tumors metastatic to bone, and osteoporosis inducedby glucocorticoid treatment; coronary restenosis; and certain microbialinfections including those associated with microbial pathogens selectedfrom adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp.,Bordetella pertussis, and group A Streptococcus.

This invention also relates to a method of (and to a pharmaceuticalcomposition for) treating abnormal cell growth in a mammal whichcomprise an amount of a compound of formula 1, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents, which amounts aretogether effective in treating said abnormal cell growth.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of formula 1 in the methods and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98134915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931,788 (published Jul. 28, 1999), WO90/05719 (published May 331, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain patent application number 9912961.1 (filed Jun.3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are herein incorporatedby reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors arethose that have little or no activity inhibiting MMP-1. More preferred,are those that selectively inhibit MMP-2 and/or MMP-9 relative to theother matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in combination with thecompounds of the present invention are AG-3340, RO 32-3555, RS 13-0830,and the compounds recited in the following list:

3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionicacid;

3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide;

(2R, 3R)1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylicacid hydroxyamide;

4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide;

3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionicacid;

4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide;

3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylicacid hydroxyamide;

(2R, 3R)1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylicacid hydroxyamide;

3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionicacid;

3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionicacid;

3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide;

3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide; and

3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylicacid hydroxyamide;

and pharmaceutically acceptable salts, solvates and prodrugs of saidcompounds.

The compounds of formula 1, and the pharmaceutically acceptable salts,solvates and prodrugs thereof, can also be used in combination withsignal transduction inhibitors, such as agents that can inhibit EGFR(epidermal growth factor receptor) responses, such as EGFR antibodies,EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascularendothelial growth factor) inhibitors; and erbB2 receptor inhibitors,such as organic molecules or antibodies that bind to the erbB2 receptor,for example, HERCEPTIN™ (Genentech, Inc. of South San Francisco, Calif.,USA).

EGFR inhibitors are described in, for example in WO 95/19970 (publishedJul. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO 98/02434(published Jan. 22, 1998), and U.S. Pat. No. 5,747,498 (issued May 5,1998). EGFR-inhibiting agents include, but are not limited to, themonoclonal antibodies C225 and anti-EGFR 22Mab (ImClone SystemsIncorporated of New York, N.Y., USA), the compounds ZD-1839(AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc.of Annandale, N.J., USA), and OLX-103 (Merck & Co. of WhitehouseStation, N.J., USA), VRCTC-310 (Ventech Research) and EGF fusion toxin(Seragen Inc. of Hopkinton, Mass.).

VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of SouthSan Francisco, Calif., USA), can also be combined with a compound offormula 1. VEGF inhibitors are described in, for example in WO 99/24440(published May 20, 1999), PCT International Application PCT/IB99100797(filed May 3, 1999), in WO 95/21613 (published Aug. 17, 1995), WO99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504 (issued Nov.10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat. No.5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issued Mar.23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), WO 99/10349(published Mar. 4, 1999), WO 97/32856 (published Sep. 12, 1997), WO97/22596 (published Jun. 26, 1997), WO 98/54093 (published Dec. 3,1998), WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (publishedApr. 8, 1999), and WO 98/02437 (published Jan. 22, 1998), all of whichare herein incorporated by reference in their entirety. Other examplesof some specific VEGF inhibitors are IM862 (Cytran Inc. of Kirkland,Wash., USA); anti-VEGF monoclonal antibody of Genentech, Inc. of SouthSan Francisco, Calif.; and angiozyme, a synthetic ribozyme from Ribozyme(Boulder, Colorado) and Chiron (Emeryville, Calif.).

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), andthe monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of TheWoodlands, Tex., USA) and 2B-1 (Chiron), may be administered incombination with a compound of formula 1. Such erbB2 inhibitors includethose described in WO 98/02434 (published Jan. 22, 1998), WO 99/35146(published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17,1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458(issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2,1999), each of which is herein incorporated by reference in itsentirety. ErbB2 receptor inhibitors useful in the present invention arealso described in U.S. Provisional Application No. 60/117,341, filedJan. 27, 1999, and in U.S. Provisional Application No. 60/117,346, filedJan. 27, 1999, both of which are herein incorporated by reference intheir entirety.

Other antiproliferative agents that may be used with the compounds ofthe present invention include inhibitors of the enzyme farnesyl proteintransferase and inhibitors of the receptor tyrosine kinase PDGFr,including the compounds disclosed and claimed in the following U.S.patent applications Ser. No. 09/221946 (filed Dec. 28, 1998); Ser. No.09/454058 (filed Dec. 2, 1999); Ser. No. 09/501163 (filed Feb. 9, 2000);Ser. No. 09/539930 (filed Mar. 31, 2000); Ser. No. 09/202796 (filed May22, 1997); Ser. No. 09/384339 (filed Aug. 26, 1999); and Ser. No.09/383755 (filed Aug. 26, 1999); and the compounds disclosed and claimedin the following U.S. provisional patent applications: 60/168207 (filedNov. 30, 1999); 60/170119 (filed Dec. 10, 1999); 60/177718 (filed Jan.21, 2000); 60/168217 (filed Nov. 30, 1999), and 60/200834 (filed May 1,2000). Each of the foregoing patent applications and provisional patentapplications is herein incorporated by reference in their entirety.

A compound of formula 1 may also be used with other agents useful intreating abnormal cell growth or cancer, including, but not limited to,agents capable of enhancing antitumor immune responses, such as CTLA4(cytotoxic lymphocite antigen 4) antibodies, and other agents capable ofblocking CTLA4; and anti-proliferative agents such as other farnesylprotein transferase inhibitors, for example the farnesyl proteintransferase inhibitors described in the references cited in the“Background” section, supra. Specific CTLA4 antibodies that can be usedin the present invention include those described in U.S. ProvisionalApplication 60/113,647 (filed Dec. 23, 1998) which is hereinincorporated by reference in its entirety.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes theabnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; (4) anytumors that proliferate by receptor tyrosine kinases; (5) any tumorsthat proliferate by aberrant serine/threonine kinase activation; and (6)benign and malignant cells of other proliferative diseases in whichaberrant serine/threonine kinase activation occurs.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The term “halo”, as used herein, unless otherwise indicated, includesfluoro, chloro, bromo or iodo. Preferred halo groups are fluoro andchloro.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, cyclic(including mono- or multi-cyclic moieties) or branched moieties. It isunderstood that for said alkyl group to include cyclic moieties it mustcontain at least three carbon atoms.

The term “cycloalkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having cyclic(including mono- or multi-cyclic) moieties.

The term “alkenyl”, as used herein, unless otherwise indicated, includesalkyl groups, as defined above, having at least one carbon-carbon doublebond.

The term “alkynyl”, as used herein, unless otherwise indicated, includesalkyl groups, as defined above, having at least one carbon-carbon triplebond.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl.

The term “alkoxy”, as used herein, unless otherwise indicated, includes—O-alkyl groups wherein alkyl is as defined above.

The term “4 to 10 membered heterocyclic”, as used herein, unlessotherwise indicated, includes aromatic and non-aromatic heterocyclicgroups containing one or more heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem. Non-aromatic heterocyclic groups include groups having only 4atoms in their ring system, but aromatic heterocyclic groups must haveat least 5 atoms in their ring system. The heterocyclic groups includebenzo-fused ring systems and ring systems substituted with one or moreoxo moieties. An example of a 4 membered heterocyclic group isazetidinyl (derived from azetidine). An example of a 5 memberedheterocyclic group is thiazolyl and an example of a 10 memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the compoundslisted above, may be C-attached or N-attached where such is possible.For instance, a group derived from pyrrole may be pyrrol-1-yl(N-attached) or pyrrol-3-yl (C-attached).

The term “Me” means methyl, “Et” means ethyl, and “Ac” means acetyl.

In the definition of X¹ above, the —(CR¹R²)_(m)— and (CR¹⁶R¹⁷)_(k)moieties, and other similar moieties, as indicated above, may vary intheir definition of R1, R2, R16 and R17 for each iteration of thesubscript (ie, m, k, etc) above 1. Thus, —(CR¹R²)_(m)— may include—CH₂C(Me)(Et)- where m is 2.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of the present invention. The compounds ofthe present invention that are basic in nature are capable of forming awide variety of salts with various inorganic and organic acids. Theacids that may be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds of are those that form non-toxicacid addition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.The compounds of the present invention that include a basic moiety, suchas an amino group, may form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above.

Those compounds of the present invention that are acidic in nature arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal or alkalineearth metal salts and, particularly, the calcium, magnesium, sodium andpotassium salts of the compounds of the present invention.

Certain functional groups contained within the compounds of the presentinvention can be substituted for bioisosteric groups, that is, groupswhich have similar spatial or electronic requirements to the parentgroup, but exhibit differing or improved physicochemical or otherproperties. Suitable examples are well known to those of skill in theart, and include, but are not limited to moieties described in Patini etal., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.

The compounds of the present invention have asymmetric centers andtherefore exist in different enantiomeric and diastereomeric forms. Thisinvention relates to the use of all optical isomers and stereoisomers ofthe compounds of the present invention, and mixtures thereof, and to allpharmaceutical compositions and methods of treatment that may employ orcontain them. The compounds of formula 1 may also exist as tautomers.This invention relates to the use of all such tautomers and mixturesthereof.

The subject invention also includes isotopically-labelled compounds, andthe pharmaceutically acceptable salts, solvates and prodrugs thereof,which are identical to those recited in formula 1, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of the presentinvention, prodrugs thereof, and pharmaceutically acceptable salts ofsaid compounds or of said prodrugs which contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically-labelled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of formula 1 of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

This invention also encompasses pharmaceutical compositions containingand methods of treating bacterial infections through administeringprodrugs of compounds of the formula 1. Compounds of formula 1 havingfree amino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of formula 1. Theamino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

DETAILED DESCRIPTION OF THE INVENTION

General synthetic methods which may be referred to for preparing thecompounds of the present invention are provided in U.S. Pat. No.5,747,498 (issued May 5, 1998), U.S. patent application Ser. No.08/953078 (filed Oct. 17, 1997), WO 98/02434 (published Jan. 22, 1998),WO 98/02438 (published Jan. 22, 1998), WO 96/40142 (published Dec. 19,1996), WO 96/09294 (published Mar. 6, 1996), WO 97/03069 (published Jan.30, 1997), WO 95/19774 (published Jul. 27, 1995) and WO 97/13771(published Apr. 17, 1997). Additional procedures are referred to in U.S.patent application Ser. No. 09/488,350 (filed Jan. 20, 2000) and Ser.No. 09/488,378 (filed Jan. 20, 2000). The foregoing patents and patentapplications are incorporated herein by reference in their entirety.Certain starting materials may be prepared according to methods familiarto those skilled in the art and certain synthetic modifications may bedone according to methods familiar to those skilled in the art. Astandard procedure for preparing 6-iodoquinazolinone is provided inStevenson, T. M., Kazmierczak, F., Leonard, N. J., J. Org. Chem. 1986,51, 5, p. 616. Palladium-catalyzed boronic acid couplings are describedin Miyaura, N., Yanagi, T., Suzuki, A. Syn. Comm. 1981, 11, 7, p. 513.Palladium catalyzed Heck couplings are described in Heck et. al. OrganicReactions, 1982, 27, 345 or Cabri et. al. in Acc. Chem. Res. 1995, 28,2. For examples of the palladium catalyzed coupling of terminal alkynesto aryl halides see: Castro et. al. J. Org. Chem. 1963, 28, 3136. orSonogashira et. al. Synthesis, 1977, 777. Terminal alkyne synthesis maybe performed using appropriately substituted/protected aldehydes asdescribed in: Colvin, E. W. J. et. al. Chem. Soc. Perkin Trans. I, 1977,869; Gilbert, J. C. et. al. J. Org. Chem., 47, 10, 1982; Hauske, J. R.et. al. Tet. Lett., 33, 26, 1992, 3715; Ohira, S. et. al. J. Chem. Soc.Chem. Commun., 9, 1992, 721; Trost, B. M. J. Amer. Chem. Soc., 119, 4,1997, 698; or Marshall, J. A. et. al. J. Org. Chem., 62, 13, 1997, 4313.

Alternatively terminal alkynes may be prepared by a two step procedure.First, the addition of the lithium anion of TMS (trimethylsilyl)acetylene to an appropriately substituted/protected aldehyde as in:Nakatani, K. et. al. Tetrahedron, 49, 9, 1993, 1901. Subsequentdeprotection by base may then be used to isolate the intermediateterminal alkyne as in Malacria, M.; Tetrahedron, 33, 1977, 2813; orWhite, J. D. et. al. Tet. Lett., 31, 1, 1990, 59.

Starting materials, the synthesis of which is not specifically describedabove, are either commercially available or can be prepared usingmethods well known to those of skill in the art.

In each of the reactions discussed or illustrated in the Schemes above,pressure is not critical unless otherwise indicated. Pressures fromabout 0.5 atmospheres to about 5 atmospheres are generally acceptable,and ambient pressure, i.e., about 1 atmosphere, is preferred as a matterof convenience.

With reference to Scheme 1 above, the compound of formula 1 may beprepared by coupling the compound of formula D wherein R⁴ and R⁵ aredefined above, with an amine of formula E wherein R¹, R³ and R¹¹ are asdefined above, in an anhydrous solvent, in particular a solvent selectedfrom DMF (N,N-dimethylformamide), DME (ethylene glycol dimethyl ether),DCE (dichloroethane) and t-butanol, and phenol, or a mixture of theforegoing solvents, a temperature within the range of about 50-150° C.for a period ranging from 1 hour to 48 hours. The heteroaryloxyanilinesof formula E may be prepared by methods known to those skilled in theart, such as, reduction of the corresponding nitro intermediates.Reduction of aromatic nitro groups may be performed by methods outlinedin Brown, R. K., Nelson, N. A. J. Org. Chem. 1954, p. 5149; Yuste, R.,Saldana, M, Walls, F., Tet. Lett. 1982, 23, 2, p. 147; or in WO96/09294, referred to above. Appropriate heteroaryloxy nitrobenzenederivatives may be prepared from halo nitrobenzene precursors bynucleophilic displacement of the halide with an appropriate alcohol asdescribed in Dinsmore, C. J. et. al., Bioorg. Med. Chem. Lett., 7, 10,1997, 1345; Loupy, A. et. al., Synth. Commun., 20, 18, 1990, 2855; orBrunelle, D. J., Tet. Lett., 25, 32, 1984, 3383. Compounds of formula Ein which R¹ is a C₁-C₆ alkyl group may be prepared by reductiveamination of the parent aniline with R¹CH(O). The compound of formula Dmay be prepared by treating a compound of formula C, wherein Z¹ is anactivating group, such as bromo, iodo, —N₂, or —OTf (which is —OSO₂CF₃),or the precursor of an activating group such as NO₂, NH₂ or OH, with acoupling partner, such as a terminal alkyne, terminal alkene, vinylhalide, vinyl stannane, vinylborane, alkyl borane, or an alkyl oralkenyl zinc reagent. The compound of formula C can be prepared bytreating a compound of formula B with a chlorinating reagent such asPOCl₃, SOCl₂ or ClC(O)C(O)CIIDMF in a halogenated solvent at atemperature ranging from about 60° C. to 150° C. for a period rangingfrom about 2 to 24 hours. Compounds of formula B may be prepared from acompound of formula A wherein Z¹ is as described above and Z² is NH₂,C₁-C₆ alkoxy or OH, according to one or more procedures described in WO95/19774, referred to above.

Any compound of formula 1 can be converted into another compound offormula 1 by standard manipulations to the R⁴ group. These methods areknown to those skilled in the art and include a) removal of a protectinggroup by methods outlined in T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Second Edition, John Wiley and Sons, NewYork, 1991; b) displacement of a leaving group (halide, mesylate,tosylate, etc) with a primary or secondary amine, thiol or alcohol toform a secondary or tertiary amine, thioether or ether, respectively; c)treatment of phenyl (or substituted phenyl) carbamates with primary ofsecondary amines to form the corresponding ureas as in Thavonekham, Bet. al. Synthesis (1997), 10, p 1189; d) reduction of propargyl orhomopropargyl alcohols or N-BOC protected primary amines to thecorresponding E-allylic or E-homoallylic derivatives by treatment withsodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) as in Denmark, S.E.; Jones, T. K. J. Org. Chem. (1982) 47, 4595-4597 or van Benthem, R.A. T. M.; Michels, J. J.; Speckamp, W. N. Synlett (1994), 368-370; e)reduction of alkynes to the corresponding Z-alkene derivatives bytreatment hydrogen gas and a Pd catalyst as in Tomassy, B. et. al.Synth. Commun. (1998), 28, p 1201 f) treatment of primary and secondaryamines with an isocyanate, acid chloride (or other activated carboxylicacid derivative), alkyl/aryl chloroformate or sulfonyl chloride toprovide the corresponding urea, amide, carbamate or sulfonamide; g)reductive amination of a primary or secondary amine using R¹CH(O); andh) treatment of alcohols with an isocyanate, acid chloride (or otheractivated carboxylic acid derivative), alkyl/aryl chloroformate orsulfonyl chloride to provide the corresponding carbamate, ester,carbonate or sulfonic acid ester.

The compounds of the present invention may have asymmetric carbon atoms.Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixtures into a diastereomricmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomeric mixtures andpure enantiomers are considered as part of the invention.

The compounds of formulas 1 that are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate the compound of formula 1 from the reaction mixture asa pharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent, such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is readily obtained. The desired acidsalt can also be precipitated from a solution of the free base in anorganic solvent by adding to the solution an appropriate mineral ororganic acid.

Those compounds of formula 1 that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline-earth metalsalts and particularly, the sodium and potassium salts. These salts areall prepared by conventional techniques. The chemical bases which areused as reagents to prepare the pharmaceutically acceptable base saltsof this invention are those which form non-toxic base salts with theacidic compounds of formula 1. Such non-toxic base salts include thosederived from such pharmacologically acceptable cations as sodium,potassium calcium and magnesium, etc. These salts can easily be preparedby treating the corresponding acidic compounds with an aqueous solutioncontaining the desired pharmacologically acceptable cations, and thenevaporating the resulting solution to dryness, preferably under reducedpressure. Alternatively, they may also be prepared by mixing loweralkanolic solutions of the acidic compounds and the desired alkali metalalkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction and maximum yields of the desired finalproduct. Since a single compound of the present invention may includemore than one acidic or basic moieties, the compounds of the presentinvention may include mono, di or tri-salts in a single compound.

The compounds of the present invention are potent inhibitors of the erbBfamily of oncogenic and protooncogenic protein tyrosine kinases, inparticular erbB2, and thus are all adapted to therapeutic use asantiproliferative agents (e.g., anticancer) in mammals, particularly inhumans. In particular, the compounds of the present invention are usefulin the prevention and treatment of a variety of human hyperproliferativedisorders such as malignant and benign tumors of the liver, kidney,bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic,lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, headand neck, and other hyperplastic conditions such as benign hyperplasiaof the skin (e.g., psoriasis) and benign hyperplasia of the prostate(e.g., BPH). It is, in addition, expected that a compound of the presentinvention may possess activity against a range of leukemias and lymphoidmalignancies.

The compounds of the present invention may also be useful in thetreatment of additional disorders in which aberrant expressionligand/receptor interactions or activation or signalling events relatedto various protein tyrosine kinases, are involved. Such disorders mayinclude those of neuronal, glial, astrocytal, hypothalamic, and otherglandular, macrophagal, epithelial, stromal, and blastocoelic nature inwhich aberrant function, expression, activation or signalling of theerbB tyrosine kinases are involved. In addition, the compounds of thepresent invention may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases that are inhibited by the compounds ofthe present invention.

The in vitro activity of the compounds of formula 1 may be determined bythe following procedure.

The c-erbB2 kinase assay is similar to that described previously inSchrang et. al. Anal. Biochem. 211, 1993, p233-239. Nunc MaxiSorp96-well plates are coated by incubation overnight at 37° C. with 100 mLper well of 0.25 mg/mL Poly (Glu, Tyr) 4:1 (PGT) (Sigma Chemical Co.,St. Louis, Mo.) in PBS (phosphate buffered saline). Excess PGT isremoved by aspiration, and the plate is washed three times with washbuffer (0.1% Tween 20 in PBS). The kinase reaction is performed in 50 mLof 50 mM HEPES (pH 7.5) containing 125 mM sodium chloride, 10 mMmagnesium chloride, 0.1 mM sodium orthovanadate, 1 mM ATP, 0.48 mg/mL(24 ng/well) c-erbB2 intracellular domain. The intracellular domain ofthe erbB2 tyrosine kinase (amino acids 674-1255) is expressed as a GSTfusion protein in Baculovirus and purified by binding to and elutionfrom glutathione coated beads. The compound in DMSO (dimethylsulfoxide)is added to give a final DMSO concentration of about 2.5%.Phosphorylation was initiated by addition of ATP (adenosinetriphosphate) and proceeded for 6 minutes at room temperature, withconstant shaking. The kinase reaction is terminated by aspiration of thereaction mixture and subsequent washing with wash buffer (see above).Phosphorylated PGT is measured by 25 minutes of incubation with 50 mLper well HRP-conjugated PY54 (Oncogene Science Inc. Uniondale, N.Y.)antiphosphotyrosine antibody, diluted to 0.2 mg/mL in blocking buffer(3% BSA and 0.05% Tween 20 in PBS). Antibody is removed by aspiration,and the plate is washed 4 times with wash buffer. The colorimetricsignal is developed by addition of TMB Microwell Peroxidase Substrate(Kirkegaard and Perry, Gaithersburg, Md.), 50 mL per well, and stoppedby the addition of 0.09 M sulfuric acid, 50 mL per well. Phosphotyrosineis estimated by measurement of absorbance at 450 nm. The signal forcontrols is typically 0.6-1.2 absorbance units, with essentially nobackground in wells without the PGT substrate and is proportional to thetime of incubation for 10 minutes. Inhibitors were identified byreduction of signal relative to wells without inhibitor and IC₅₀ valuescorresponding to the concentration of compound required for 50%inhibition are determined. The compounds exemplified herein whichcorrespond to formula 1 have IC₅₀ values of <10 μM against erbB2 kinase.

The activity of the compounds of formula 1, in vivo, can be determine bythe amount of inhibition of tumor growth by a test compound relative toa control. The tumor growth inhibitory effects of various compounds aremeasured according to the method of Corbett T. H., et al., “TumorInduction Relationships in Development of Transplantable Cancers of theColon in Mice for Chemotherapy Assays, with a Note on CarcinogenStructure”, Cancer Res., 35, 2434-2439 (1975) and Corbett T. H., et al.,“A Mouse Colon-tumor Model for Experimental Therapy”, Cancer Chemother.Rep. (Part 2)”, 5, 169-186 (1975), with slight modifications. Tumors areinduced in the left flank by subcutaneous (sc) injection of 1-5 millionlog phase cultured tumor cells (murine FRE-ErbB2 cells or human SK-OV3ovarian carcinoma cells) suspended in 0.1 ml RPMl 1640 medium. Aftersufficient time has elapsed for the tumors to become palpable (100-150mm3 in size/5-6 mm in diameter) the test animals (athymic female mice)are treated with test compound (formulated at a concentration of 10 to15 mg/ml in 5 Gelucire) by the intraperitoneal (ip) or oral (po) routeof administration once or twice daily for 7 to 10 consecutive days. Inorder to determine an anti-tumor effect, the tumor is measured inmillimeters with a Vernier caliper across two diameters and the tumorsize (mm3) is calculated using the formula: Tumor size(mm3)=(length×[width]2)/2, according to the methods of Geran, R. I., etal. “Protocols for Screening Chemical Agents and Natural ProductsAgainst Animal Tumors and Other Biological Systems”, Third Edition,Cancer Chemother. Rep., 3, 1-104 (1972). Results are expressed aspercent inhibition, according to the formula: Inhibition(%)=(TuW_(control)−TuW_(test))/TuW_(control)×100%. The flank site oftumor implantation provides reproducible dose/response effects for avariety of chemotherapeutic agents, and the method of measurement (tumordiameter) is a reliable method for assessing tumor growth rates.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to about 7 g/day,preferably about 0.2 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied as a sole therapy or may involve oneor more other anti-tumour substances, for example those selected from,for example, mitotic inhibitors, for example vinblastine; alkylatingagents, for example cis-platin, carboplatin and cyclophosphamide;anti-metabolites, for example 5-fluorouracil, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

Where HPLC chromatography is referred to in the preparations andexamples below, the general conditions used, unless otherwise indicated,are as follows. The column used is a ZORBAX™ RXC18 column (manufacturedby Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. Thesamples are run on a Hewlett Packard-1100 system. A gradient solventmethod is used running 100 percent ammonium acetate/acetic acid buffer(0.2 M) to 100 percent acetonitrile over 10 minutes. The system thenproceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutesand then 100 percent buffer solution for 3 minutes. The flow rate overthis period is a constant 3 mL/minute.

In the following examples and preparations, “Et” means ethyl, “AC” meansacetyl, “Me” means methyl, “ETOAC” or “ETOAc” means ethyl acetate, “THF”means tetrahydrofuran, and “Bu” means butyl.

Method A: Synthesis of[3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine(1):

4-(4-Chloro-qui nazolin-6-ylethynyl)-piperidine-1-carboxylic AcidTert-butyl Ester:

A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester(1.12 g, 5.35 mmol), 4-chloro-6-iodoquinazoline (1.35 g, 4.65 mmol),dichlorobis(triphenylphosphine) palladium(II) (0.16 g, 0.23 mmol),copper(I) iodide (0.044 g, 0.23 mmol), and diisopropylamine (0.47 g,4.65 mmol) in anhydrous THF (20 mL) was stirred at room temperatureunder nitrogen for 2 hours. After concentration, the residue wasdissolved in CH₂Cl₂ (100 mL), washed with aqueous NH₄Cl and brine, driedover sodium sulfate, and concentrated to give the crude product as brownoil. Purification by silica gel column using 20% EtOAc in hexaneafforded 1.63 g (94%) of the title compound as a sticky, yellow oil: ¹HNMR (CDCl₃) δ 1.45 (s, 9H), 1.67-1.75 (m, 2H), 1.87-1.92 (m, 2H), 2.84(m, 1H), 3.20-3.26 (m, 2H), 3.78 (br d, 2H), 7.88 (dd, 1H), 7.97 (d,1H), 8.26 (d, 1H), 9.00 (s, 1H).

[3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine:4-(4-Chloro-quinazolin-6-ylethynyl)-piperidine-1-carboxylic acidtert-butyl ester (80 mg, 0.21 mmol) and3-Methyl-4-(pyridin-3-yloxy)-phenylamine (43 mg, 0.21 mmol) were mixedtogether in tert-butanol (1 mL) and dichloroethane (1 mL) and heated ina sealed vial at 90° C. for 20 minutes. The reaction was cooled down andHCl (gas) was bubbled through for 5 minutes. EtOAC was then addedwhereupon yellow precipitation occurred. The precipitate was collectedand dried to afford the desired product[3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amineas a yellow solid (96 mg, 95%). ¹H NMR (CDCl₃) δ 2.01 ((m, 2H), 2.22 (m,2H), 2.35(s, 3H), 3.20 (m, 2H), 3.45(m, 2H), 7.28 (d, 1H, J=8.7 Hz),7.75(dd, 3H, J1=8.7, J2=8.7 Hz), 8.06 (dd, J=8.7), 8.10 (dd, J1=J2=8.7Hz), 8.17 (m, 1 H), 8.60 (d, 1H, J=5.4 Hz), 8.80 (s, 1H), 8.89 (s, 1H).MS: M+1, 436.6.

Method B: Synthesis of2-Chloro-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-guinazolin-6-yl}-prop-2-ynyl)-acetamide(2):

2-Chloro-N-[3-(4-chloro-quinazolin-6-yI)-prop-2-ynyl]-acetamide:2-Chloro-N-prop-2-ynyl-acetamide (385 mg; 2.93 mmol) and4-chloro-6-iodoquinazoline (850 mg; 1 equiv.) were dissolved in dry THFand diisopropylamine (296 mg; 0.41 mL; 1 equiv.). To this mixture wasadded 0.04 equivalents of copper iodide (22 mg) and Pd(PPh₃)₂Cl₂ (82mg). The reaction was stirred at room temperature under a nitrogenatmosphere overnight (˜20 hrs). The solvent was then removed in vacuoand the residue dissolved in CH₂Cl₂. This solution was transferred to aseparatory funnel and washed with 1× saturated NH₄Cl, brine, dried overNa₂SO₄ and the solvent removed in vacuo. The product was purified bysilica gel chromatography eluting with 1:1 Hexanes/EtOAc and collectingfractions with an Rf=0.25.2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide wasobtained as an off white solid (454 mg; 53%). ¹H NMR (400 MHz; CDCl₃) δ4.12 (2H, s), 4.40 (2H, d, J=5.2 Hz), 7.91-7.93 (1H, dd, J=2, 6.8 Hz),8.00 (1H, d, J=8.4 Hz), 8.34 (1H, d, J=1.6 Hz), 9.03 (1H, s). Irms (M+):294.0, 296.0, 298.1.

2-Chloro-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide:A mixture of2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide (0.90 g,3.05 mmol) and 3-Methyl-4-(pyridin-3-yloxy)-phenylamine (0.61 g, 3.05mmol) in ^(t)BuOH/DCE (5.0/5.0 mL) was refluxed under nitrogen for 40minutes and concentrated. The residue was dissolved in MeOH (2.0 mL) andadded to EtOAc with vigorous stirring to precipitate the HCI saltproduct as tan solid which was collected by vacuum-filtration, rinsedwith EtOAc, and further dried to give 1.24 g (82%) of2-Chloro-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide:¹H NMR (CD₃OD) δ 2.27 (s, 3H), 4.09 (s, 2H), 4.29 (s, 2H), 7.07 (d, 1H),7.51 (m, 2H), 7.60 (d, 1H), 7.70 (s, 1H), 7.78 (d, 1H), 8.05 (d, 1H),8.32 (m, 2H), 8.67 (s, 1H), 8.75 (s, 1H); MS m/z (MH⁺) 458.0.

Method C: Synthesis of2-Dimethylamino-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide(3):

2-Dimethylamino-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide:To a solution of2-Chloro-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide(99 mg, 0.20 mmol) in MeOH (5 mL) was added a solution dimethylamine inTHF (2 mL, 4.0 mmol). The resulting solution was refluxed under nitrogenfor 1 hour. After concentration, the residue was further dried,dissolved in MeOH (1.0 mL), and treated with HCl gas for 3 minutes. Theresulting solution was added to EtOAc with vigorous stirring toprecipitate the HCl salt product as yellow solid which was collected byvacuum-filtration, rinsed with EtOAc, and further dried to give 110 mg(99%) of the title compound. ¹H NMR (CD₃OD) δ 2.30 (s, 3H), 2.96 (s,6H), 4.03 (s, 2H), 4.37 (s, 2H), 7.27 (d, 1H), 7.72 (dt, 1H), 7.81(m,1H), 7.84 (d, 1H), 8.03 (dd, 1H), 8.06 (d, 1H), 8.13 (dd, 1H), 8.59 (d,1H), 8.68 (s, 1H), 8.81 (s, 1H), 8.84 (s, 1H); MS m/z (MH⁺) 467.3.

Method D: Synthesis of1-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-guinazolin-6-yI}-prop-2-ynyl)-3-methyl-urea(4):

1-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-3-methyl-urea:A mixture of(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamicacid phenyl ester (0.1 g, 0.18 mmol) prepared by Method B, methyl amine(2.0M methanol solution, 1 mL, 2 mmol) and DMSO (0.5 mL) was stirred at80° C. overnight. The solvents were removed under vacuum (GeneVac HT-8)and the residue was re-dissolved in MeOH (˜1 mL). HCl gas was bubbledthrough the solution and EtOAc resulting in precipitation of the desiredproduct. The title compound (80 mg, 90% yield) was obtained byfiltration as a yellow solid. ¹HNMR (400 MHz, CD₃OD) δ 2.72 (3H,s), 2.76(3H, s), 4.19 (2H, s), 7.49 (1H, d, J=9 Hz), 7.84 (1H, d, J=2 Hz), 7.86(1H, d, J=2 Hz), 7.92 (1H, d, J=9 Hz), 8.12 (2H, m, J=2 Hz), 8.16 (1H,d, J=2.4 Hz), 8.60 (1H, d, J=3.2 Hz), 8.74 (1H, d, J=1.2 Hz), 8.87 (1H,s ). LRMS (M⁺): 473.0, 475.0, 476.0.

Method E: Synthesis of3{-4-[3-Methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-en-1-ol(5):

3-{4-[3-Methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-en-1-ol.To a solution of 0.56 g (1.47 mmol) of3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-yn-1-ol(prepared by Method B) in 6 mL of dry tetrahydrofuran at 0° C. was added0.73 mL of a 65% weight toluene solution of sodiumbis(2-methoxyethoxy)aluminum hydride (Red-Al, 2.35 mmol) in 1 mL of THF.The reaction was stirred at room temperature for 3 hours. Upon recoolingto 0° C. an additional 0.73 mL of the Red-Al solution in 1 mL of THF wasadded. After stirring for 1 hour at room temperature, the mixture wasquenched with the dropwise addition of 10% aqueous potassium carbonateand extracted with ethyl acetate. The organic extracts were dried oversodium sulfate, filtered and evaporated to give 650 mg. Chromatographyon 90 g silica gel, eluting with 96:4:0.1chloroform/methanol/concentrated ammonium hydroxide afforded 268 mg ofthe title compound. ¹H NMR (d₆ DMSO): δ 9.79 (s, 1), 8.57 (m, 2), 8.35(m, 2), 8.01 (m, 1), 7.80 (m, 3), 7.41 (m, 1), 7.29 (m, 1), 7.07 (d,J=8.7 Hz, 1), 6.77 (d, J=16.2 Hz, 1), 6.67 (m, 1), 5.04 (t, J=5.6 Hz,1), 4.23 (m, 2), 2.23 (s, 3).

Method F: Synthesis of[3-Methyl-4-(pyridin-3-yloxy)-phenyl]-[6-(3-morpholin-4-yl-propenyl)-guinazolin-4-yl]-amine(6):

[3-Methyl-4-(pyridin-3-yloxy)-phenyl]-[6-(3-morpholin-4-yl-propenyl)-quinazolin-4-yl]-amine.To a suspension of 0.035 g (0.091 mmol) of3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-en-1-olin 0.5 mL of methylene chloride and 1 mL of ethylene dichloride wasadded 1 mL of thionyl chloride. The reaction was heated at 100° C. for 1hour and the solvents were evaporated to provide[6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine[MS: M⁺ 403.1] which was dissolved in THF and used directly in the nextreaction. To the solution of[6-(3-chloro-propenyl)-quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-aminewas added 0.10 mL of morpholine and 0.044 mL of triethylamine. Themixture was heated at 85° C. for 16 hours, cooled to room temperature,and partitioned between 10% aqueous potassium carbonate and ethylacetate. The aqueous layer was further extracted with ethyl acetate andthe combined organics were dried and evaporated to yield 57 mg ofmaterial. The product was purified on a silica gel prep plate, elutingwith 96:4:0.1 chloroform/methanol/concentrated ammonium hydroxide toafford 26 mg of the title compound; ¹H NMR (CDCl₃): δ 8.71 (s, 1), 8.33(m, 2), 7.94 (s, 1), 7.80 (m, 2), 7.69 (s, 1), 7.58 (m, 1), 7.20 (m, 1),6.94 (d, J8.7 Hz, 1), 6.68 (d, J=15.8 Hz, 1), 6.46 (m, 1), 3.79 (m, 4),3.26(m, 2), 2.63 (m, 4), 2.25 (s, 3).

Method G: Synthesis ofE-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-guinazolin-6-yl}-allyI)-acetamide(7):

E-(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-carbamicacid tert-butyl ester: To a solution of 7.53 mL of a 65% weight toluenesolution of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al, 24.2mmol) in 90 mL of tetrahydrofuran at 0° C. was added 5.0 g of(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamicacid tert-butyl ester as a solid. The reaction was stirred at 0° C. for2 hours, quenched with 10% aqueous potassium carbonate and extractedwith ethyl acetate. The combined organics were dried and evaporated. Thecrude material was purified on 115 g of silica gel, eluting with 80%ethyl acetate/hexanes to afford 4.42 g ofE-(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-carbamicacid tert-butyl ester. ¹H NMR (CDCl₃): δ 8.66 (s, 1), 8.24 (m, 1), 8.03(m, 2), 7.77-7.65 (m, 3), 7.13 (m, 2), 6.97 (d, J=8.7 Hz, 1), 6.54 (d,1), 6.35 (m, 1), 4.9 (m, 1), 3.90 (m, 2), 2.52 (s, 3), 1.46 (s, 9).

E-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine.To a solution of 4.42 g ofE-(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-carbamicacid tert-butyl ester in 21 mL of tetrahydrofuran was added 21 mL of 2 Nhydrochloric acid. The mixture was heated at 60° C. for 3 hours, cooledto room temperature and basified with 10% aqueous potassium carbonate.Methylene chloride was added to the aqueous mixture and a solidprecipitated. The solid was filtered and dried to yield 2.98 g ofE-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine.¹H NMR (d₆ DMSO): δ 8.62 (s, 1), 8.53 (m, 1), 8.26 (m, 2), 7.99 (m, 1),7.89 (m, 1), 7.77 (m, 1), 7.30 (m, 3), 6.67 (m, 2), 3.44 (m, 2), 2.47(s, 3).

E-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide.A mixture of 14.4 μL (0.25 mmol) of acetic acid and 40.3 mg (0.33 mmol)of dicyclohexylcarbodiimide in 2 mL of methylene chloride were stirredfor 10 minutes and treated with 100.3 mg ofE-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine.The reaction was allowed to stir at room temperature overnight. Theprecipitate which formed was filtered and chromatographed on silica gel,eluting with 6-10% methanol/chloroform to afford 106 mg of the titlecompound; mp 254-256° C.; ¹H NMR (d₆ DMSO): δ 9.88 (s, 1), 8.58 (s, 1),8.48 (m, 1), 8.20 (m, 3), 7.95 (m, 1), 7.83 (m, 1), 7.71(d, J=8.7 Hz,1), 7.24 (m, 2), 7.19 (d, J=8.7 Hz, 1), 6.61 (d, J=16.2 Hz, 1), 6.48 (m,1), 3.90 (m, 2).

Method H: E-2S-Methoxymethyl-pyrrolidine-1-carboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-ally)-amide(8):

To a stirred solution of 0.125 g (0.31 mmol) ofE-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine(prepared according to method G) in 1 mL of dichloromethane at 0° C. wasadded 60.3 μL (0.34 mmol) of Hunig's base followed by dropwise additionof a solution of 48.2 uL (0.34 mmol) of 4-chlorophenyl chloroformate in1 mL of dichloromethane. The reaction was stirred 30 minutes andevaporated under reduced pressure. The residue was dissolved in 2 mL ofdimethyl sulfoxide and 123 μL (0.94 mmol) of(S)-(+)-2-(methoxymethyl)-pyrrolidine was added neat. The reaction wasstirred for 3 hours at room temperature. The reaction was quenched into10% potassium carbonate and extracted with ethyl acetate. The organiclayer was washed several times with water and twice with brine. Theorganic layer was dried over sodium sulfate and reduced to yield thecrude material. This material was purified over 90 g of silica gel using96:4:0.1 chloroform:methanol:ammonium hydroxide as eluent to yield 75 mg(0.14 mmol) of the title compound. ¹HNMR (d₆ DMSO): δ 9.83 (s, 1), 8.56(s, 2), 8.21 (d, 1), 7.95 (d, 1), 7.80 (d, 1), 7.50 (d, 1), 7.25 (m, 2),7.01 (d, 1), 6.63 (d, 1), 6.53 (m, 1), 3.95 (m, 2), 3.40 (dd, 1), 3.28(s, 3), 2.49 (s, 3), 2.24 (s, 3), 1.85 (m, 4).

Method I:E-2-Hydroxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-isobutyramide(9):

To a solution of 0.170 g (0.42 mmol) ofE-[6-(3-amino-propenyl)-quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine(prepared according to method G) in 1 mL of dichloromethane at 0° C. wasadded 65 μL (0.47 mmol) of triethylamine followed by a solution of 65 μL(0.45 mmol) of 2-acetoxyisobutyryl chloridein 1 mL of dichloromethane.The reaction was stirred at 0° C. for 1 hour. The mixture was quenchedwith a dropwise addition of 10% potassium carbonate. The aqueous layerwas extracted with dichloromethane and the combined organics were washedwith brine, dried over sodium sulfate and evaporated. The crude materialwas purified on 90 g of silica gel eluting with 96:4:0.1chloroform/methanol /ammonium hydroxide to afford2-acetoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-isobutyramide.A solution of this material in 2 mL of methanol was treated dropwisewith a solution of 41 mg (3.02 mmol) of potassium carbonate in 0.5 mL ofwater. The solution was stirred at room temperature for 1 hour. Thereaction was evaporated and the residue was partitioned between waterand chloroform. The aqueous layer was extracted twice with chloroformand the combined organics were washed with brine, dried over sodiumsulfate and evaporated to yield 100 mg of the title compound (47%).¹HNMR (d₆ DMSO): δ 9.78 (s, 1), 8.50 (s, 1), 8.48 (s, 1), 8.15 (d, 1),7.95 (m, 2), 7.65 (m, 3), 7.21 (m, 2), 6.96 (d, 1), 6.56 (dt, 1), 3.92(t, 2), 2.46 (s, 3), 2.1.

Method J: Synthesis of Z-Cyclopropanecarboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-guinazolin-6-yl}-allyl)-amide

Z-[6-(3-Amino-propenyl)-quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine:A solution of of(3-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamicacid tert-butyl ester (1 g, 2.01 mmol) was taken up in methanol (20 ml),palladium in carbon (50 mg) added and the resulting suspension subjectedto hydrogenation at 40 psi for eight hours. Thereafter the suspensionwas filtered through a pad of celite and the filtrate concentrated invacuo to afford the Z-alkene compound. This was taken up in methanol andHCl (g) was added. Evaporation of solvent then providedZ-[6-(3-Amino-propenyl)-quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amineas its hydrochloride salt. The salt was taken up in CH₂Cl₂ and stirredwith Na₂CO₃, filtered and solvent evaporated to afford ˜700 mg of thefree amine.

¹H NMR (CD₃OD): δ 8.49 (s, 1), 8.31 (s, 1), 8.07 (m, 1), 7.78 (s, 2H),7.72 (m, 1H), 7.67 (s, 1H), 7.58 (d, J=10.5 Hz, 1H), 7.25 (m, 2H), 6.99(m 2H), 5.88 (m, 1H), 3.95 (d, J=8 Hz, 2H), 2.47 (s, 3H), 2.23 (s, 3H).MS: M+1, 399.3

Z-Cyclopropanecarboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide

Z-[6-(3-Amino-propenyl)-quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine(100 mg, 0.25 mmol) was taken up in DMF (3 ml), HATU (143 mg, 0.38 mmol)and cyclopropane carboxylic acid (36 mg, 0.42 mmol) were added and theresulting solution was allowed to stir for 18 h. Water was then added,the reaction mixture extracted with methylene chloride, the organicextract washed with brine and dried over Na₂SO4. After concentration invacuo, the crude material was subjected to purification on preparativeHPLC (reversed phase, 5-40% CH₃CN-H₂O) to afford 46 mg of the titlecompound. ¹H NMR (CD₃OD): δ 8.77 (s, 1H), 8.72 (s, 1H), 8.24 (s, 1H),8.00 (m 1H), 7.77 (m, 3H), 7.55 (m, 2H), 7.07 (d, J=10 Hz, 1H), 6.76 (d,J=13 Hz, 1H), 5.95 (m, 1H), 4.2 (br unresolved m, 2H), 2.59 (s, 3H), 2.3(s, 3H), 1.59 (br unresolved m, 1H), 1.16 (br unresolved m, 1H), 0.79(m, 3H). MS: M+1 466.3.

The following examples were prepared using the methods described above.

TABLE I Example HPLC No. Name Method LRMS RT 10(±)-[3-Methyl-4-(pyridin-3- A 436.0 4.48 yloxy)-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)- amine 11 1-(3-{4-[3-Chloro-4-(6-methyl- D499.0 5.74 pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-3-cyclopropyl-urea 12 N-(3-{7-Chloro-4-[3-chloro-4- B 492.0 6.07(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 13 N-(3-{7-Chloro-4-[3-methyl-4- B 472.2 5.79(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 14 Exo-6-Hydroxymethyl-3-aza- D 555.0 5.19bicyclo[3.1.0]hexane-3- carboxylic acid (3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 15 1-(3-{4-[3-Chloro-4-(6-methyl- D 505.0 5.65pyridin-3-yloxy)-phenyiamino]- quinazolin-6-yl}-prop-2-ynyl)-3-(2-fluoro-ethyl)-urea 16 1-(3-{4-[3-Chloro-4-(6-methyl- D 503.0 4.98pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-3-(2-hydroxy-ethyl)-urea 17 3-{4-[3-Methyl-4-(pyridin-3- A 452.0 4.01yloxy)-phenylamino]-quinazolin- ylethynyl}piperidin-3-ol 182-(2-Hydroxy-ethylsulfanyl)-N- C 500.0 4.87(3-{4-[3-methyl-4-(pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 19 N-(3-{4-[3-Chloro-4-(pyridin-3- C 520.05.15 yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-2-(2-hydroxy-ethylsulfanyl)- acetamide 20 (±)-[3-Methyl-4-(pyridin-3- A 438.04.29 yloxy)-phenyl]-(6-morpholin-2- ylethynyl-quinazolin-4-yl)-amine 212-Cyano-N-(3-{4-[3-methyl-4- B 448.9 5.18(pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- acetamide22 N-(3-{4-[3-Methyl-4-(pyridin-3- B 452.0 5.61yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-butyramide 23Pentanoic acid (3-{4-[3-methyl- B 466.0 6.02 4-(pyridin-3-Ybloxy)-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-amide 242-Methoxy-N-(3-{4-[3-methyl- B 454.0 5.244-(pyridin-3-yloxy)-phenylamino ]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 25 N-(4-{4-[3-Methyl-4-(pyridin-3- B 438.1 5.11yloxy)-phenylamino]-quinazolin- 6-yl}-but-3-ynyl)-acetamide 26[6-(4-Amino-but-1-ynyl)- A 396.1 4.04 quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine 27 N-(3-{4-[3-Methyl-4-(pyridin-3- B470.2 5.50 yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-2-methylsulfanyl-acetamide 28 3-{4-[3-Methyl-4-(pyridin-3- B 383.0 4.97yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-yn-1-ol 29[6-(3-Methoxy-prop-1-ynyl)- B 397.3 6.23 quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine 30 4-{4-[3-Methyl-4-(pyridin-3- B 397.15.17 yloxy)-phenylamino]-quinazolin- 6-yl}-but-3-yn-1-ol 312-Methyl-4-{4-[3-methyl-4- B 411.0 5.62 (pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-but-3-yn-2-ol 32 (3-{4-[3-Methyl-4-(pyridin-3- B 440.35.61 yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-carbamic acidmethyl ester 33 N-(3-{4-[3-Methyl-4-(pyridin-3- B 460.0 5.38yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)- methanesulfonamide34 N-(3-{4-[3-Methyl-4-(pyridin-3- B 424.1 4.94yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-acetamide 35[3-Methoxy-4-(pyridin-3-yloxy)- A 452.0 4.10 phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine 36 2-Chloro-N-(3-{4-[3-methyl-4- B458.0 5.52 (pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- acetamide 37 2-Methylamino-N-(3-{4-[3- C453.1 4.08 methyl-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 38 2-Dimethylamino-N-(3-{4-[3- C 467.3 4.15methyl-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 39 (±)-(6-Piperidin-3-ylethynyl- A 422.1 4.13quinazolin-4-yl)-[4-(pyridin-3- yloxy)-phenyl]-amine 40[3-Methoxy-4-(pyridin-3-yloxy)- A 452.1 4.11 phenyl]-(6-piperidin-4-quinazolin-4-yl)-amine 41 [3-Chloro-4-(pyridin-3-yloxy)- A 456.1 4.57phenyl]-(6-piperidin-4- ylethynyl-quinazolin-4-yl)-amine 42[3-Fluoro-4-(pyridin-3-yloxy)- A 440.1 4.38 phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine 43 (6-Piperidin-4-ylethynyl- A 422.14.11 quinazolin-4-yl)-[4-(pyridin-3- yloxy)-phenyl]-amine 442-Methoxy-N-(3-{4-[3-methoxy- B 470.3 4.874-(pyridin-3-yloxy)-phenylamino ]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 45 N-(3-{4-[3-Chloro-4-(pyridin-3- B 474.2 5.48yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-2-methoxy- acetamide46 N-(3-{4-[3-Fluoro-4-(pyridin-3- B 458.3 5.23yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-2-methoxy- acetamide47 [3-Methyl-4-(pyridin-2-yloxy)- A 436.0 4.52 phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine 48 2,2-Dimethyl-N-(3-{4-[3- A 452.35.60 methyl-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-propionamide 49 N-(3-{4-[3-Methyl-4-(pyridin-3- B 466.36.01 yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)- isobutyramide50 {6-[3-(2-Methoxy-ethoxy)-prop- B 441.1 6.111-ynyl]-quinazolin-4-yl}-[3- methyl-4-(pyridin-3-yloxy)- phenyl]-amine51 2-Diethylamino-N-(3-{4-[3- C 495.1 4.45 methyl-4-(pyridin-3-yloxy)-phenylamino]- quinazolin- 6-yl}-prop-2-ynyl)-acetamide 52(±)-[3-Methyl-4-(2-methyl- A 450.0 4.47 pyridin-3-yloxy)-phenyl]-(6-piperidin-3-yiethynyl- quinazolin-4-yl)-amine 53[3-Methyl-4-(2-methyl-pyridin- A 450.0 4.393-yloxy)-phenyl]-(6-piperidin- 4-ylethynyl-quinazolin-4-yl)- amine 542-Methoxy-N-(3-{4-[3-methyl- B 468.0 5.33 4-(2-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-acetamide 552-(2-Methoxy-ethoxy)-N-(3-{4-[ B 498.3 5.34[3-methyl-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 56 (±)-Tetrahydro-furan-2- B 480.0 5.45-carboxylic acid (3-{4-[3- methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-amide 57(±)-4,4-Dimethyl-5-{4- B 466.0 5.70 [3-methyl-4(pyridin-3-yloxy)-phenylamino]-quinazolin-6- ylethynyl}-oxazolidin-2-one 58{6-[4-(2-Methoxy-ethoxy)- B 455.3 6.23 but-1-ynyl]-quinazolin-4-yl}-[3-methyl-4-(pyridin-3- yloxy)-phenyl]-amine 594-{4-[3-Methyl-4-(pyridin-3- A 452.0 3.82yloxy)-phenylamino]-quinazolin- 6-ylethynyl}-piperidin-4-ol 601-Methyl-4-{4-[3-methyl-4- B 466.1 4.03 (pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylethynyl}- piperidin-4-ol 61 (±)-[3-Methyl-4-(6-methyl- A450.0 4.52 pyridin-3-yloxy)-phenyl]-(6- piperidin-3-ylethynyl-quinazolin-4-yl)-amine 62 [3-Methyl-4-(6-methyl-pyridin- A 450.0 4.493-yloxy)-phenyl]-(6-piperidin-4- ylethynyl-quinazolin-4-yl)-amine 632-Methoxy-N-(3-{4-[3-methyl- B 468.8 5.38 4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-acetamide 64[6-(4-Methoxy-but-1-ynyl)- B 411.2 6.30 quinazolin-4-yl]-[3-methyl-4-(pyridin-3-yloxy)-phenyl]- amine 65 (±)-[4-(2-Chloro-pyridin-3- A 470.04.89 yloxy)-3-methyl-phenyl]-(6- piperidin-3-ylethynyl-quinazolin-4-yl)-amine 66 Cyclopropanecarboxylic acid B 464.3 5.63(4-{4-[3-methyl-4-(pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-but-3-ynyl)-amide 67 [4-(2-Chloro-pyridin-3-yloxy)-3- A 470.0 4.86methyl-phenyl]-(6-piperidin-4- ylethynyl-quinazolin-4-yl)- amine 68N-(3-{4-[4-(2-Chloro- B 488.0 5.84 pyridin-3-yloxy)-3-methyl-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-2-methoxy- acetamide 69N-(4-{4-[3-Methyl-4-(pyridin- B 484.2 5.64 3-yloxy)-phenylamino]-quinazolin-6-yl}-but-3-ynyl)- 2-methylsulfanyl-acetamide 70[3-Chloro-4-(pyridin-3-yloxy)- B 431.1 6.67 phenyl]-[6-(4-methoxy-but-1-ynyl)-quinazolin-4-yl]- amine 71 (±)-4-{4-[3-Methyl-4-(pyridin- A 413.14.31 3-yloxy)-phenylamino]- quinazolin-6-yl}-but-3-yne- 1,2-diol 72 (±)-[3-Methyl-4-(pyridin- A 434.1 3.88 4-yloxy)-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)- amine 73 [3-Methyl-4-(pyridin-4-yloxy)- A436.1 3.91 phenyl]-(6-piperidin-4- ylethynyl-quinazolin-4-yl)- amine 742-Methoxy-N-(3-{4-[3-methyl- B 452.0 4.71 4-(pyridin-4-yloxy)-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-acetamide 752,2-Difluoro-N-(3-{4-[3- B 460.2 5.63 methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-acetamide 76N-(3-{4-[3-Chloro-4- B 482.2, 5.92 (pyridin-3-yloxy)-phenylamino]- 480.1quinazolin-6-yl}-prop-2-ynyl)- 2,2-difluoro-acetamide 77R-Pyrrolidine-2-carboxylic acid A 479.1 4.22 (3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- amide 78(±)-Tetrahydro-furan-3- B 500.0 5.39 carboxylic acid (3-{4-[3-chloro-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 79 Cyclopropanecarboxylic acid B 484.0 5.92(4-{4-[3-chloro-4-(pyridin- 3-yloxy)-phenylamino]-quinazolin-6-yl}-but-3-ynyl)- amide 80 N-(4-{4-[3-Chloro-4-(pyridin- B505.4 5.91 3-yloxy)-phenylamino]- quinazolin-6-yl}-but-3-ynyl)-2-methylsulfanyl-acetamide 81 1-(3-{4-[3-Methyl-4-(pyridin- D 501 .16.17 3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2- ynyl)-3-phenyl-urea82 1-Cyclohexyl-3-(3-{4-[3-methyl- D 507.2 6.24 4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-urea 831-(3-{4-[3-Chloro-4-(pyridin- D 528.1 6.49 3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2- ynyl)-3-cyclohexyl-urea 842-Hydroxy-N-(4-{4-[3-methyl-4- A 454.2 4.78(pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-but- 3-ynyl)-acetamide85 E-3-{4-[3-Methyl-4-(pyridin- E 385.1 4.71 3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-en-1-ol 86 E-[3-Methyl-4-(pyridin- F 454.1 4.143-yloxy)-phenyl]-[6-(3- morpholin-4-yl-propenyl)- quinazolin-4-yl]-amine87 2-Methanesulfonyl-N-(3-{4-[3- B 502.0 5.00methyl-4-(pyridin-3-yloxy)- phenylaminol-quinazolin-6-yl}-prop-2-ynyl)-acetamide 88 N-(3-{4-[3-Chloro-4- B 522.0 5.28(pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-methanesulfonyl- acetamide 89 (3-{4-[3-Methyl-4-(pyridin- B456.2 6.02 3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-thiocarbamic acid S- methyl ester 90 (3-{4-[3-Chloro-4-(pyridin-3-B 476.1 6.29 yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-thiocarbamic acid S-methyl ester 91[4-(2-Methyl-pyridin-3-yloxy)- A 436.1 4.24 phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)- amine 92 (±)-[4-(2-Methyl-pyridin-3- A 436.04.85 yloxy)-phenyl]-(6-piperidin-3- ylethynyl-quinazolin-4-yl)- amine 93N-(3-{4-[4-(2-Methyl-pyridin-3- B 424.1 4.85yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-acetamide 94N-(3-{4-[3-Methyl-4-(pyridin-3- B 452.1 5.64yloxy)-phenylamino]-quinazolin- yl}-prop-2-ynyl)-2-oxo- propionamide 95N-(3-{4-[3-Chloro-4-(pyridin- B 474.3, 5.93 3-yloxy)-phenylamino]- 472.3quinazolin-6-yl}-prop-2-ynyl)-2- oxo-propionamide 96N-(3-{4-[3-Methyl-4-(pyridin-3- B 496.2 5.56yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-malonamic acid ethylester 97 N-(3-{4-[3-Chloro-4-(pyridin-3- B 516.0 5.84yloxy)-phenylamino]-quinazolin- 6yl}-prop-2-ynyl)-malonamic acid ethylester 98 N-(1,1-Dimethyl-3-{4-[3- B 506.0 6.76methyl-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-2,2,2-trifluoro- acetamide 99 (±)-N-(1-Hydroxymethyl-3-{4-B 454.1 4.47 [3-methyl-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 100 (±)- [3-Ethynyl-4-(pyridin-3- A 446.14.33 yloxy)-phenyl]-(6-piperidin-3- ylethynyl-quinazolin-4-yl)- amine101 [3-Ethynyl-4-(pyridin-3-yloxy)- A 446.1 4.27 phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)- amine 102 3-{4-[3-Chloro-4-(pyridin- B403.1 5.43 3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-yn-1- ol 103(±)-N-(1-Hydroxymethyl-3-{4- B 468.1 4.66 [3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2- ynyl)-acetamide 104(±)-N-(3-{4-[3-Chloro-4- b 474.0 4.78 (pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-1- hydroxymethyl-prop-2-ynyl)- acetamide 1052,2-Difluoro-N-(3-{4-[3- B 474.2 5.83 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-acetamide 1062-Methanesulfonyl-N-(3-{4-[3- B 516.0 5.20 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- acetamide 1072-Fluoro-N-(3-{4-[3-methyl-4- B 441.8 5.27(pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop- 2-ynyl)-acetamide108 N-(3-{4-[3-Chloro-4-(pyridin-3- B 461.9 5.55yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-2- fluoro-acetamide109 2-Fluoro-N-(3-{4-[3-methyl-4- B 456.2 5.47(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 110 N-(3-{4-[3-Ethynyl-4-(pyridin- B 464.15.16 3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-methoxy-acetamide 111 2-Methoxy-N-(3-{4-[4-(2- B 454.2 5.15methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 112 [4-(2-Chloro-pyridin-3-yloxy)- A 456.1 4.64phenyl]-(6-piperidin-4- ylethynyl-quinazolin-4-yl)- amine 113(±)-[4-(2-Chloro-pyridin-3- A 456.0 4.67 yloxy)-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)- amine 114 N-(3-{4-[4-(2-Chloro-pyridin-3- B474.0 5.54 yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-2-methoxy-acetamide 115 N-(3-{4-[4-(2-Chloro-pyridin-3- B 444.0 5.25yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-acetamide 116N-(3-{4-[3-Ethynyl-4-(pyridin- B 434.1 4.88 3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- acetamide 1171-(2-Chloro-ethyl)-3-(3-{4-[3- D 487.2 5.46 methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-urea 118(±)-[3-Fluoro-4-(2-methyl- A 454.1 4.57 pyridin-3-yloxy)-phenyl]-(6-piperidin-3-ylethynyl- quinazolin-4-yl)-amine 119[3-Fluoro-4-(2-methyl-pyridin-3- A 454.1 4.56yloxy)-phenyl]-(6-piperidin-4- ylethynyl-quinazolin-4-yl)-amine 120N-(3-{4-[3-Fluoro-4-(2-methyl- B 442.1 5.19pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- acetamide121 N-(3-{4-[3-Chloro-4-(6-methyl- B 458.0 5.48pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- acetamide122 [3-Chloro-4-(6-methyl-pyridin- A 470.0 4.783-yloxy)-phenyl]-(6-piperidin- 4-ylethynyl-quinazolin-4-yl)- amine 123(±)-[3-Chloro-4-(6-methyl- A 470.0 4.80 pyridin-3-yloxy)-phenyl]-(6-piperidin-3-ylethynyl- quinazolin-4-yl)-amine 124 Acetic acid3-{4-[3-methyl-4- B 425.1 6.34 (pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl ester 125 3-{4-[3-Methyl-4-(6-methyl- B397.2 5.31 pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-yn-1-ol 126 Acetic acid 3-{4-[3-methyl-4- B439.1 6.57 (6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl ester 127 Acetic acid 3-{4-[3-chloro-4- B 445.1 6.66(pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl ester 1282-Hydroxy-N-(3-{4-[3-methyl-4- A 454.2 4.81 (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-acetamide 129N-(3-{4-[3-Methyl-4-(6-methyl- B 438.0 5.20pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- acetamide130 R-Pyrrolidine-2-carboxylic acid A 493.0 4.42 (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 131 2-(2-Hydroxy-ethylsulfanyl)- C 513.9 5.07N-(3-{4-[3-methyl-4-(6- methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-acetamide 132(±)-2-Methanesulfinyl-N- B 499.9 4.71 (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- acetamide133 (3-{4-[3-Methyl-4-(6-methyl- B 469.9 6.25pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-thiocarbamic acid S-methyl ester 134 (±)-Tetrahydro-furan-3- B 494.05.31 carboxylic acid (3-{4-[3-methyl- 4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-amide 135N-(3-{4-[3-Methyl-4-(6-methyl- B 465.9 5.87pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-oxo-propionamide 136 N-(3-{4-[3-Methyl-4-(6-methyl- B 510.0 5.77pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- malonamicacid ethyl ester 137 (6-Piperidin-4-ylethynyl- A 422.2 3.48quinazolin-4-yl)-[4-(pyridin- 2-yloxy)-phenyl]-amine 138(±)-(6-Piperidin-3-ylethynyl- A 422.2 3.51quinazolin-4-yl)-[4-(pyridin-2- yloxy)-phenyl]-amine 139N-(3-{4-[4-(Pyridin-2-yloxy)- B 410.1 3.81phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-acetamide 1402-Methylamino-N-(3-{4-[3- C 467.0 4.26 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-acetamide 1412-Dimethylamino-N-(3-{4-[3- C 481.0 4.26 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-acetamide 142(±)-N-(3-{4-[3-Chloro-4-(6- B 488.0 4.99 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-1-hydroxymethyl-prop-2- ynyl)-acetamide143 N-(3-{4-[3-Chloro-4-(6- C 501 .0 4.83 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-2- dimethylamino-acetamide144 N-(3-{4-[3-Chloro-4-(6-methyl- B 488.0 5.79pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-methoxy-acetamide 145 N-(3-{4-[3-Chloro-4-(6-methyl- B 476.0 5.79pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-fluoro-acetamide 146 N-(3-{4-[3-Chloro-4-(6-methyl- B 494.0 6.14pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2,2-difluoro-acetamide 147 E-3-{4-[3-Chloro-4-(pyridin-3- E 405.1 5.04yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-en-1-ol 1482-Methoxy-N-(3-{4-[4-(pyridin- B 440.8 4.05 2-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)- acetamide 1491-Ethyl-3-(3-{4-[3-methyl-4-(6- D 467.2 5.36 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-urea 1501-(3-{4-[3-Chloro-4-(pyridin-3- D 473.2 5.45 yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-3- ethyl-urea 1511-Ethyl-3-(3-{4-[3-methyl-4- D 453.1 5.16(pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- urea 1521-(3-{4-[3-Chloro-4-(6-methyl- D 487.1 5.60pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-3-ethyl-urea 153 (±)-2-Hydroxy-N-(3-{4-[3- A 454.1 4.79methyl-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-propionamide 154 N-(3-{4-[3-Methyl-4-(2-methyl- B 466.15.85 pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-oxo-propionamide 155 N-(3-{4-[3-Methyl-4-(2-methyl- B 438.1 5.18pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- acetamide156 (±)-2-Hydroxy-N-(3-{4-[3- A 468.0 4.98 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)- propionamide 157(±)-N-(3-{4-[3-Chloro-4- A 488.0 5.32 (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-2-hydroxy- propionamide 158N-(3-{4-[3-Methyl-4-(6- C 536.2 4.46 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-2-(4-methyl-piperazin-1-yl)-acetamide 159 2-[Bis-(2-methoxy-ethyl)- C 569.1 5.93amino]-N-(3-{4-[3-methyl-4- (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-acetamide 1602-(2-Hydroxy-ethylamino)-N- C 483.0 4.11 (3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-acetamide 161N-(3-{4-[3-Chloro-4-(pyridin-3- C 487.0 4.65yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-2-dimethylamino-acetamide 162 N-(3-{4-[3-Chloro-4-(pyridin-3- C 473.0 4.42yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-2-methylamino-acetamide 163 N-(3-{4-[3-Chloro-4-(6-methyl- C 487.1 4.60pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-methylamino-acetamide 164 N-(3-{4-[3-Chloro-4-(6-methyl- A 474.0 5.13pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-hydroxy-acetamide 165 1-(3-{4-[3-Chloro-4-(6-methyl- D 501.8 5.98pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-3-isopropyl-urea 166 1-Isopropyl-3-(3-{4-[3-methyl- D 481.0 5.694-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea 167 Morpholine-4-carboxylic acid D 509.1 5.27(3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 168 N-(3-{4-[3-Chloro-4-(6-methyl-C 543.3 5.64 pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-2- morpholin-4-yl-acetamide 169N-(3-{4-[3-Methyl-4-(6-methyl- C 522.8 5.37pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-morpholin-4-yl-acetamide 170 [6-(3-Amino-prop-1-ynyl)- A 396.3 4.05quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy)- phenyl]-amine171 E-[6-(3-Amino-propenyl)- G 398.2 3.87 quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenyl]-amine 172 E-[6-(3-Amino-propenyl)- G418.0 4.26 quinazolin-4-yl]-[3-chloro-4- (6-methyl-pyridin-3-yloxy)-phenyl]-amine 173 2-Hydroxy-N-(3-{4-[3-methyl-4- A 468.1 5.04(pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-isobutyramide 174 2-Hydroxy-N-(3-{4-[3-methyl- A 482.1 5.244-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- isobutyramide 175 N-(3-{4-[3-Chloro-4-(6-methyl- A502.0, 5.55 pyridin-3-yloxy)-phenylamino]- 504.0quinazolin-6-yl}-prop-2-ynyl)- 2-hydroxy-isobutyramide 176[6-(3-Amino-prop-1-ynyl)- A 416.2 4.25 quinazolin-4-yl]-[3-chloro-4-(6-methyl-pyridin-3-yloxy)- phenyl]-amine 177 N-(3-{4-[3-Methyl-4-(6- C535.3 5.99 methyl-pyridin-3-yloxy)- phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-(2,2,2- trifluoro-ethylamino)-acetamide 1781,1-Dimethyl-3-(3-{4-[3- D 467.3 5.36 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- urea 1793-(3-{4-[3-Chloro-4-(6-methyl- D 515.0 6.32 pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-1,1-diethyl- urea 1803-(3-{4-[3-Chloro-4-(6- D 487.1 5.70 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-1,1-dimethyl- urea 181E-N-(3-{4-[3-Methyl-4- G 440.3 4.74 (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- allyl)-acetamide 182E-2-Methoxy-N-(3-{4-[3- G 470.1 5.05 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-allyl)-acetamide 183Morpholine-4-carboxylic acid D 529.0 5.58 (3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 184 Pyrrolidine-1-carboxylic acid D 513.0 6.00(3-{4-[3-chloro-4-(6- methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-amide 1851-(3-{4-[3-Chloro-4-(6- D 473.0 5.37 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-3-methyl-urea 1861-(3-{4-[3-Chloro-4-(6- D 501.0 6.03 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl }-prop-2-ynyl)-3-propyl-urea 1871-tert-Butyl-3-(3-{4-[3- D 515.0 6.56 chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-urea 1882S-Hydroxy-N-(3-{4-[3-methyl- B 468.0 4.95 4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)- propionamide 1891-(3-{4-[3-Chloro-4-(6-methyl- D 540.7 6.19pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-3-(2,2,2-trifluoro-ethyl)-urea 190 (±)-Azetidine-2-carboxylic acid A465.2 4.21 (3-{4-[3-methyl-4-(pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 191 (±)-Azetidine-2-carboxylic acid A 479.34.41 (3-{4-[3-methyl-4-(6- methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-amide 192(±)-Azetidine-2-carboxylic acid A 499.3 4.70(3-{4-[3-chloro-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 193 1-Hydroxy- B 480.0 5.20cyclopropanecarboxylic acid (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- amide 194N-(3-{4-[3-Methyl-4-(6-methyl- B 452.1 5.55pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-propionamide 195 N-(3-{4-[3-Methyl-4-(6-methyl- B 466.1 5.88pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- butyramide196 N-(3-{4-[3-Methyl-4-(6-methyl- B 466.1 5.88pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-isobutyramide 197 2-Ethoxy-N-(3-{4-[3-methyl-4- B 482.1 5.89(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 198 N-(3-{4-[3-Methyl-4-(6-methyl- B 484.05.76 pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-2-methylsulfanyl-acetamide 199 Cyclopropanecarboxylic acid B 464.1 5.76(3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 200 Cyclobutanecarboxylic acid B478.1 6.07 (3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 201 [6-(3-Amino-prop-1-ynyl)- A382.1 4.02 quinazolin-4-yl]-[3-methyl- 4-(pyridin-3-yloxy)-phenyl]-amine 202 Isoxazole-5-carboxylic acid B 491.0 5.78(3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 203 N-Methyl-N-(3-{4-[3-methyl-4- B452.5 5.79 (6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 204 2-Methoxy-N-(1-methyl-3- B 481.9 5.86{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- acetamide 205 N-(1,1-Dimethyl-3-{4-[3- B466.2 5.82 methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 206 2R-Hydroxy-N-(3-{4-[3-methyl- B 468.04.95 4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-propionamide 207 E-Cyclopropanecarboxylic acid G 466.15.41 (3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide 208 E-N-(3-{4-[3-Methyl-4-(6- G 454.1 5.07methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-proponamide 209 E-2-Ethoxy-N-(3-{4-[3-methyl- G 484.0 5.544-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-acetamide 210 E-(±)-2-Methoxy-N-(3-{4-[3- G 484.1 5.45methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-propionamide 211 E-2-Fluoro-N-(3-{4-[3-methyl- G 458.1 5.484-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-acetamide 212 2-Methoxy-N-(1-{4-[3-methyl- B 508.0 6.174-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-ylethynyl}-cyclobutyl)- acetamide 213 N-(1-{4-[3-Methyl-4-(6- B 478.05.90 methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-ylethynyl}-cyclobutyl)- acetamide 214 E-N-(3-{4-(3-Chloro-4-(6- G 478.05.55 methyl-pyridin-3-yloxy)- phenylamino]- quinazolin-6-yl}-allyl)-2-fluoro-acetamide 215 E-Cyclopropanecarboxylic acid G 485.7 5.77(3-{4-[3-chloro-4-(6- methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- allyl)-amide 216[6-(1-Amino-cyclobutylethynyl)- A 436.0 4.87quinazolin-4-yl]-[3-methyl-4- (6-methyl-pyridin-3-yloxy)- phenyl]-amine217 (±)-2-Methoxymethyl- D 537.1 6.13 pyrrolidine-1-carboxylic acid(3-{4-[3-methyl-4 (6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 218 Piperazine-1-carboxylic acid 0508.1 4.28 (3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazoiin-6-yl}-prop-2- ynyl)-amide 219 3-(3-{4-[3-Chloro-4-(6- D 531.05.41 methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-1-ethyl-1-(2- hydroxy-ethyl)-urea 220 [6-(1-Amino- A 422.15.11 cyclopropylethynyl)-quinazolin- 4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine 221 E-3-{4-[3-Methyl-4-(6- E 399.2 4.93methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6- yl}-prop-2-en-1-01222 N-(3-{4-[3-Chloro-4-(6- B 532.0 5.86 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-2-(2-methoxy-ethoxy)-acetamide 223 N-(3-{4-[3-Chloro-4-(6- B 486.0 6.17methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-2-oxo- propionamide 224 N-(3-{4-[3-Chloro-4-(6- C 534.05.57 methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-2-(2-hydroxy- ethylsulfanyl)-acetamide 225N-(3-{4-[3-Chloro-4-(6- B 504.0 6.04 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-2- methylsulfanyl-acetamide226 Pyrrolidine-2R-carboxylic acid A 513.4 4.86(3-{4-[3-chloro-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 227 Pyrrolidine-2R-carboxylic acidA 499.0 4.45 (3-{4-[3-chloro-4-(pyridin- 3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 228 (±)-2-Methanesulfinyl-N-(3-{4-B 486.1 4.52 [3-methyl-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 229 (±)-2-Methanesulfinyl-N-(3-{4- B 506.04.81 [3-chloro-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide 230 (±)-Tetrahydro-furan-3- B 480.1 5.11carboxylic acid (3-{4-[3- methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-amide 2312-Hydroxy-N-(3-{4-[3-methyl- A 440.3 4.60 4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-acetamide 2322-Ethoxy-N-(3-{4-[3-methyl-4- B 467.9 5.62 (pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-acetamide 233[3-Methyl-4-(pyridin-3-yloxy)- A 436.6 4.35 phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)- amine 234 Cyclobutanecarboxylic acid B 464.05.78 (3-{4-[3-methyl-4-(pyridin- 3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 235 Cyclopropanecarboxylic acid B450.0 5.44 (3-{4-[3-methyl-4-(pyridin- 3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 236 [3-Methyl-4-(pyridin-2-yloxy)-A 436.0 4.64 phenyl]-(6-piperidin-3- ylethynyl-quinazolin-4-yl)- amine237 (6-Azetidin-3-ylethynyl- A 407.9 4.10 quinazolin-4-yl)-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine 238 N-(1,1-Dimethyl-3-{4- B 481 .9 5.96[3-methyl-4-(pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-2-methoxy- acetamide 239 2-[4-(3-{4-[3-Methyl-4- A495.4 4.10 (pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-piperazin-1-yl]-ethanol 240 (±)-2-Methoxy-N-(1-methyl-3- B 467.95.57 {4-[3-methyl-4-(pyridin- 3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- acetamide 241[3-Methyl-4-(pyridin-3-yloxy)- A 436.0 4.48 phenyl]-(6-piperidin-3R-ylethynyl-quinazolin-4-yl)- amine 242 [3-Methyl-4-(pyridin-3-yloxy)- A436.0 4.48 phenyl]-(6-piperidin-3S- ylethynyl-quinazolin-4-yl)- amine243 (±)-[3-Methyl-4-(pyridin- A 422.0 4.303-yloxy)-phenyl]-(6-pyrrolidin- 3-ylethynyl-quinazolin-4-yl)- amine

TABLE II Example HPLC No. Name Method LRMS RT 2441-(2-Methoxy-ethyl)-1-methyl-3- D 511.1 5.61(3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- urea 245 (±)-2-Hydroxymethyl- D 523.15.19 pyrrolidine-1-carboxylic acid (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- amide 246(±)-3-Hydroxy-pyrrolidine- D 509.1 4.75 1-carboxylic acid (3-{4-[3-methyl-4-(6-methyl-pyridin- 3-yloxy)-phenylamino]-quinazolin-6-yl)-prop-2-ynyl)- amide 247 Cis- and trans-2,5-Dimethyl- D521.1 6.38, pyrrolidine-1-carboxylic acid 6.28(3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 248 1-Isobutyl-1-methyl-3-(3- D509.1 6.45 {4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2- ynyl)-urea 249 N-(1-{4-[3-Methyl-4-(6- B 464.05.46 methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-ylethynyl}-cyclopropyl)- acetamide 250 2-Methoxy-N-(1-{4-[3- B 5.76493.7 methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-ylethynyl}-cyclopropyl)- acetamide 251 E-N-(3-{4-[3-Chloro-4- G 474.05.53 (6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-propionamide 252 E-N-(3-{4-[3-Chloro-4- C 504.0 5.67(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-2-methoxy-propionamide 253 E-N-(3-{4-[3-Chloro-4- G 489.7 5.52(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-2-methoxy-acetamide 254 E-N-(3-{4-[3-Chloro-4- G 504.0 5.89(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-2-ethoxy-acetamide 255 (3-{4-[3-Methyl-4-(6- B 496.3 7.11methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-carbamic acid tert- butyl ester 2562-(R)-Hydroxy-N-(3-{4-[3- B 468.0 5.04 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)- propionamide 257Cyclobutanecarboxylic acid B 498.0, 6.36 (3-{4-[3-chloro-4-(6-methyl-500.0 pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-amide 258 N-(3-{4-[3-Chloro-4-(6- B 472.0, 5.86 methyl-pyridin-3-yloxy)-474.0 phenylamino]-quinazolin-6-yl)- prop-2-ynyl)-propionamide 259Cyclopropanecarboxylic acid B 484.0, 6.06 (3-{4-[3-chloro-4-(6- 486.0methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 260 N-(3-{4-[3-Chloro-4-(6- B 486.1, 6.17methyl-pyridin-3-yloxy)- 488.1 phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-isobutyramide 261 (±)-N-(3-{4-[3-Chloro B 502.0, 6.004-(6-methyl-pyridin-3-yloxy)- 504.0 phenylamino]-quinazolin-6-yl)-prop-2-ynyl)-2-methoxy- propionamide 262 (±)-2-Methoxy-N-(3-{4- B 482.15.73 [3-methyl-4-(6-methyl-pyridin- 3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- propionamide 2635-Oxo-pyrrolidine-2R-carboxylic B 507.1 4.73 acid (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 264 E-1-Hydroxy- I 482.0 4.65 cyclopropanecarboxylicacid (3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide 265 E-2S-Hydroxy-N-(3-{4-[3- I 470.1 4.56methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-allyl)- propionamide 266 E-2R-Hydroxy-N-(3-{4-[3- I470.1 4.60 methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-allyl)- propionamide 267 E-2-Hydroxy-N-(3-{4-[3- I456.1 4.51 methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-allyl)- acetamide 268 1-Cyanomethyl-3-(3-{4-[3- D 478.15.26 methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- urea 269 1-Cyclobutyl-3-(3-{4-[3- D 492.85.90 methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- urea 270 1,1,3-Trimethyl-3-(3-{4-[3- D481 .1 6.30 methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- urea 271 1-(3-{4-[3-Chloro-4-(6- D 501.16.52 methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-1,3,3- trimethyl-urea 2721-Ethyl-1-(2-hydroxy-ethyl)-3- D 511.1 5.20 (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea 273 (±)-3-Dimethylamino- D 536.1 4.40pyrrolidine-1-carboxylic acid (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- amide 274Morpholine-4-carboxylic acid D 523.4 5.58 (1-methyl-3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 275 Exo-6-Amino-3-aza- D 520.9 4.28bicyclo[3.1.0]hexane- 3-carboxylic acid (3-{4-[3-methyl-4-(6-methyl-pyridin- 3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 276 Exo-6-Hydroxymethyl-3-aza- D535.1 4.98 bicyclo[3.1.0]hexane-3- carboxylic acid (3-{4-[3-methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 277 (3-{4-[3-Methyl-4-(6- D 439.8 4.81methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea 278 E-N-(3-{4-[3-Chloro-4-(6- I 476.0 4.86methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-2-hydroxy-acetamide 279 Piperazine-1-carboxylic acid D 536.1 4.74(1,1-dimethyl-3-{4-[3-methyl- 4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-amide 2801-(1,1-Dimethyl-3-{4-[3- D 495.3 6.11 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-3-ethyl- urea 281Morpholine-4-carboxylic acid D 537.3 6.02 (1,1-dimethyl-3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 282 1,3-Dimethyl-1-(3-(4-[3-methyl- D 467.1 5.514-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea 283 N-(3-{4-[3-Chloro-4-(6- B 5.02, 5.74methyl-pyridin-3-yloxy)- 5.04 phenylamino]-quinazolin-6-yl)-1,1-dimethyl-prop-2-ynyl)-2- hydroxy-acetamide 284N-(1,1-Dimethyl-3-{4-[3- B 482.2 5.46 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-2-hydroxy- acetamide285 E-1,1-Diethyl-3-(3-{4-[3- H 497.1 5.72 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino] quinazolin-6-yl}-allyl)-urea 286E-Pyrrolidine-1-carboxylic acid H 495.1 5.40 (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6- yl}-allyl)-amide 287E-1-Ethyl-3-(3-{4-[3-methyl- H 469.1 4.80 4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-allyl)-urea 288 E-Morpholine-4-carboxylicacid H 511.1 4.75 acid (3-{4-[3-methyl-4-(6- methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-allyl)-amide 289(±)-1-Ethyl-1-(2-hydroxy- D 525.1 5.51 ethyl)-3-(1-methyl-3-{4-[3-methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea 290 (±)-1-Ethyl-3-(1-methyl-3-{ D 481.1 5.68{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2- ynyl)-urea 291 4-Methyl-piperazine-1- D 522.34.44 carboxylic acid(3-{4-[3- methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}- prop-2-ynyl)-amide 292N-(3-{4-[3-Chloro-4-(6- B 483.1 5.73 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-2-cyano-acetamide 2932-Cyano-N-(3-{4-[3-methyl-4- B 463.1 5.44 (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-acetamide 294E-N-(3-{4-[3-Methyl-4-(6- G 486.3 5.33 methyl-pyridin-3-yloxy)-phenylamlno]-quinazolin-6- yl}-allyl)-2-methylsulfanyl- acetamide 295E-5-Oxo-tetrahydro-furan-2R- G 510.2 5.58 carboxylic acid(3-{4-[3-methyl- 4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-allyl)-amide 296E-N-(3-{4-[3-Methyl-4-(6- G 476.0 5.36 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-allyl)-methanesulfonamide 297(±)-5-{4-[3-Methyl-4- B 466.1 5.22 (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- ylethynyl}-morpholin-3-one 298E-N-(3-{4-[3-Chloro-4-(6- I 490.1 5.06 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-allyl)-2S-hydroxy- propionamide 299E-1-Hydroxy- I 502.2 5.24 cyclopropanecarboxylic acid(3-{4-[3-chloro-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide 300 E-N-(3-{4-[3-Chloro-4-(6- I 504.2 5.24methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6- yl}-allyl-2-hydroxy-isobutyramide 301 (±)-E-N-(3-{4-[3-Chloro-4- I 490.0 5.07(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6- yl}-allyl)-2-hydroxy-propionamide 302 2R-Amino-N-(3-{4-[3-chloro- A 487.1 4.544-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-propionamide 303 2R-Amino-N-(3-{4-[3- A 467.2 4.35methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- propionamide 304 (±)-4-{4-[3-Methyl-4-(6-452.2 5.40 methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-ylethynyl}-oxazolidin-2-one 305 (±)-E-3,3,3-Trifluoro-2- I 524.1 5.52hydroxy-N-(3-{4-[3-methyl-4- (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl }-allyl)-propionamide 306(±)-E-2-Hydroxy-3-methyl- I 498.2 5.49 N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-butyramide 307 (±)-2-Methoxymethyl- D 557.1 6.42pyrrolidine-1-carboxylic acid (3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)- amide 308(±)-2-Hydroxymethyl- D 543.2 5.61 pyrrolidine-1-carboxylic acid(3-{4-[3-chloro-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl- amide 309 (±)-1-(3-{4-[3-Chloro-4- D 529.26.87 (6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-3-(1,2-dimethyl- propyl)-urea 310 (±)-1-(3-{4-[3-Chloro-4-D 529.2 6.89 (6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-3-(1,1- dimethyl-propyl)-urea 311(±)-1-(3-{4-[3-Chloro-4- D 531.1 5.41 (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-3-(1-hydroxymethyl-propyl)-urea 312 1-(3-{4-[3-Chloro-4-(6- D 529.1 6.63methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-3-(1-ethyl-propyl)-urea 313 (±)-1-sec-Butyl-3-(3-{4-[3- D 515.1 6.32chloro-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea 314 (±)-1-(1,1-Dimethyl-propyl)- D 509.2 6.603-(3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- urea 315 (±)-1-(1-Hydroxymethyl- D 511.25.13 propyl)-3-(3-{4-[3-methyl-4- (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-urea 3161-(1-Ethyl-propyl)-3-(3-{4-[3- D 509.3 6.35methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea 317 (±)-1-sec-Butyl-3-(3-{4-[3- D 495.3 6.07methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea 318 Azetidine-1-carboxylic acid D 479.2 5.46(3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 319 1-(1,2-Dimethyl-propyl)-3-(3- D509.2 6.36 {4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- urea 320 Piperidine-1-carboxytic acid D507.3 6.21 (3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)- amide 321 E-Pyridine-2-carboxylic acid G503.3 6.11 (3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide 322 E-2-Isopropoxy-N-(3-{4-[3- G 498.35.94 methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-allyl)- acetamide 323 E-N-(3-{4-[3-Methyl-4-(6- G 538.16.51 methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-benzenesulfonamide 324 E-Ethanesulfonic acid (3-{4- G 490.35.62 [3-methyl-4-(6-methyl-pyridin- 3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide 325 E-1H-Imidazole-4-carboxylic G 492.35.53 acid (3-{4-[3-methyl-4-(6- methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-allyl)-amide 326 E-Isoxazole-5-carboxylicacid G 493.2 5.41 (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-allyl)-amide 327E-Pyrrolidine-1-carboxylic acid H 515.2 5.77(3-{4-[3-chloro-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide 328 E-Morpholine-4-carboxylic acid H 531.1 5.20 (3-{4-[3-chloro-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide 329 E-N-(3-{4-[3-Chloro-4-(6- G 506.1 5.81methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-2-methylsulfanyl- acetamide 330 E-5-Oxo-tetrahydro-furan-2R-G 530.2 5.44 carboxylic acid (3-{4- [3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-allyl)-amide 331E-N-(3-{4-[3-Chloro-4-(6- G 530.2 6.34 methyl-pyrdin-3-yloxy)-phenylamino]-quinazolin-6- yl}-allyl)-2- cyclopropylmethoxy-acetamide332 (±)-E-N-(3-{4-[3-Chloro-4- I 518.2 5.73 (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- allyl)-2-hydroxy-3-methyl- butyramide 333E-N-(3-{4-[3-Chloro-4-(6- G 496.1 5.72 methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- allyl)-methanesulfonamide 334E-2R-Hydroxymethyl- H 525.2 4.91 pyrrolidine-1-carboxylic acid(3-{4-[3-methyl-4-(6-methyl- pyridin-3-yloxy)-phenylamino]quinazolin-6-yl}-allyl)-amide 335 E-2S-Hydroxymethyl- H 525.2 4.92pyrrolidine-1-carboxylic acid (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-allyl)-amide 336E-2-Cyclopropylmethoxy-N- G 510.3 6.00 (3{4[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}allyl)- acetamide 337E-1-Isopropyl-3-(3-{4-[3- H 483.2 5.33 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-allyl)-urea 338Azetidine-1-carboxylic acid D 499.2 5.73 (3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2- ynyl)-amide 339Piperazine-1-carboxylic acid D 528.2 4.65 (3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}prop-2- ynyl)-amide 3402-Methoxy-N-(3-{7-methoxy- B 498.2 5.47 4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}prop-2-ynyl)- acetamide341 N-(3-{4-[3-Chloro-4- B 518.2 5.76 (6-methyl-pyridin-3-yloxy)-phenylamino]-7-methoxy- quinazolin-6-yl}-prop-2-ynyl)-2-methoxy-acetamide 342 3-(3-{4-[3-Chloro-4-(6- D 531.2 5.92methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-1-(2-methoxy- ethyl)-1-methyl-urea 343N-(3-{7-Methoxy-4-[3- B 468.2 5.21 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2- ynyl)-acetamide 344N-(3-{4-[3-Chloro-4-(6- B 488.2 5.50 methyl-pyridin-3-yloxy)-phenylamino]-7-methoxy- quinazolin-6-yl}-prop-2-ynyl)- acetamide 3451,1-Diisopropyl-3-(3-{7- D 553.3 6.79 methoxy-4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea 346 (±)-2-Methyl-piperidine-1- D 521.3 6.53carboxylic acid (3-{4-[3-methyl- 4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-amide 347E-Azetidine-2S-carboxylic G 481.3 4.10 acid (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6- yl}-allyl)-amide 348E-1-Amino- G 481.3 4.40 cyclopropanecarboxylic acid(3-{4-[3-methyl-4-(6- methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}- allyl)-amide 349 E-2-Amino-N-(3-{4-[3- G483.3 4.12 methyl-4-(6-methyl-pyridin-3- yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-isobutyramide 350 E-5-Oxo-pyrrolidine-2R- G 509.2 4.45carboxylic acid (3-{4-[3- methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-allyl)-amide 351E-2R-Amino-N-(3-{4-[3- G 469.3 4.09 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-allyl)-propionamide 352E-2S-Amino-N-(3-{4-[3- G 469.3 4.09 methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}- allyl)-propionamide 353E-5-Oxo-pyrrolidine-2R- G 509.2 4.42 carboxylic acid (3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-amide 354 E-Isoxazole-5-carboxylic acid G 513.0 5.86(3-{4-[3-chloro-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl) amide 355 E-3-(3-{4-[3-Chloro-4-(6- H 517.2 6.11methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6-yl}-allyl)-1,1-diethyl-urea 356 E-Pyridine-2-carboxyiic acid G 523.16.47 (3-{4-[3-chloro-4-(6-methyl- pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)- amide 357 N-(3-{4-[3-Methyl-4-(6- B 474.2 5.66methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-methanesulfonamide 358 N-(3-{4-[3-Chloro-4-(6- B 494.1 5.93methyl-pyridin-3-yloxy)- phenylamino]-quinazolin-6- yl}-prop-2-ynyl)-methanesulfonamide

TABLE II Example mass No. Name method spec RT 359Z-Cyclopropanecarboxylic acid (3-{4-[3- J 466.3 4.65methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide 360Z-N-(3-{4-[3-Methyl-4-(6-methyl-pyridin-3- J 440.3 5.56yloxy)-phenylamino]-quinazolin-6-yl}-allyl)- acetamide 361Z-N-(3-{4-[3-Methyl-4-(6-methyl-pyridin-3- J 468.3 6.75yloxy)-phenylamino]-quinazolin-6-yl}-allyl)- isobutyramide 3623-{4-[3-Methyl-4-(6-methyl-pyridin-3- B 454.3 5.93yloxy)-phenylamino]-quinazolin-6-yl}-prop- 2-ynyl)-carbamic acid methylester 363 (3-{4-[3-Chloro-4-(6-methyl-pyridin-3- B 474.2, 6.20yloxy)-phenylamino]-quinazolin-6-yl}-prop- 476.2 2-ynyl)-carbamic acidmethyl ester 364 3-{4-[3-Chloro-4-(6-methyl-pyridin-3- B 517.3 7.34yloxy)-phenylamino]-quinazolin-6-yl}-prop- 2-ynyl)-carbamic acidtert-butyl ester 365 E-(3-{4-[3-Methyl-4-(6-methyl-pyridin-3- G 498.27.01 yloxy)-phenylamino]-quinazolin-6-yl}-allyl)- carbamic acidtert-butyl ester 366 3-Methyl-pyridine-2-carboxylic acid (3-{4- G 517.26.39 [3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide 367E-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3- G 558.2 6.83yloxy)-phenylamino]-quinazolin-6-yl}-allyl)- benzenesulfonamide 3682-Fluoro-N-(3-{4-[3-methyl-4-(2-methyl- B 457.2 4.92pyrimidin-5-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-acetamide369 [3-Methyl-4-(2-methyl-pyrimidin-5-yloxy)- A 451.5 4.09phenyl]-(6-piperidin-4-ylethynyl-quinazolin- 4-yl)-amine 3702-Methoxy-N-(3-{4-[3-methyl-4-(2-methyl- B 469.3 4.86pyrimidin-5-yloxy)-phenylamino]- quinazolin-6-yl}-prop-2-ynyl)-acetamide371 E-2-Methoxy-N-(3-{4-[3-methyl-4-(2- G 471.3 4.71methyl-pyrimidin-5-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide 3722-Methoxy-N-(3-{4-[3-methyl-4-(pyrimidin- B 455.4 4.795-yloxy)-phenylamino]-quinazolin-6-yl}- prop-2-ynyl)-acetamide 373N-(3-{4-[3-Methyl-4-(pyrimidin-5-yloxy)- B 453.1 5.16phenylamino]-quinazolin-6-yl}-prop-2- ynyl)-isobutyramide 3743-Methyl-isoxazole-5-carboxylic acid (3-{4- B 492.1 5.27[3-methyl-4-(pyrimidin-5-yloxy)- phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide 375 N-(3-{4-[3-Methyl-4-(pyrimidin-5-yloxy)- B 461.1 4.92phenylamino]-quinazolin-6-yl}-prop-2- ynyl)-methanesulfonamide 376(±)-[3-Methyl-4-(pyrimidin-5-yloxy)- A 437.2 4.016phenyl]-(6-piperidin-3-ylethynyl-quinazolin- 4-yl)-amine 3772-Methoxy-N-methyl-N-(3-{4-[3-methyl-4- B 468.3 5.52(pyridin-3-yloxy)-phenylamino]-quinazolin- 6-yl}-prop-2-ynyl)-acetamide378 E-N-(3-{4-[3-Methyl-4-(pyridin-3-yloxy)- G 426.2 5.02phenylamino]-quinazolin-6-yl}-allyl)- acetamide 379E-2-Methoxy-N-(3-{4-[3-methyl-4-(pyridin- G 456.2 5.273-yloxy)-phenylamino]-quinazolin-6-yl}- allyl)-acetamide 380E-(3-{4-[3-Methyl-4-(pyridin-3-yloxy)- G 442.3 5.60phenylamino]-quinazolin-6-yl}-allyl)- carbamic acid methyl ester 381E-N-(3-{4-[3-Methyl-4-(pyridin-3-yloxy)- G 462.0 5.29phenylamino]-quinazolin-6-yl}-allyl)- methanesulfonamide 382E-Cyclopropanecarboxylic acid (3-{4-[3- G 452.2 5.48methyl-4-(pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-allyl)-amide383 E-Pyridine-2-carboxylic acid (3-{4-[3- G 489.1 6.15methyl-4-(pyridin-3-yloxy)-phenylamino]- quinazolin-6-yl}-allyl)-amide384 E-1-Ethyl-3-(3-{4-[3-methyl-4-(pyridin-3- H 455.3 5.16yloxy)-phenylamino]-quinazolin-6-yl}-allyl)- urea

Utilizing methods A through J and the appropriate starting materials(prepared according to methodology known in the art), the followingcompounds, which are part of the present invention, may be prepared:

Z-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl-}-allyl)-acetamide

E-2-(2-Fluoro-ethoxy)-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide

Z-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-2-fluoro-acetamide

2-Hydroxy-N-(1-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylethynyl}-cyclopropyl)-acetamide

E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-isobutyramide

1-Ethyl-3-(1-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylethynyl}-cyclopropyl)-urea

1-Ethyl-3-[1-(2-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-ethyl)-cyclopropyl]-urea

3-Methoxy-azetidine-1-carboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide

N-(3-{7-(2-Methoxy-ethoxy)-4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide

E-1-Methoxy-cyclopropanecarboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide

N-(3-{4-[3-Methyl-4-(2-methyl-pyrimidin-5-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide

(+)-E-1-(2-Fluoro-ethyl)-3-(1-methyl-3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-urea

E-N-[1-(2-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-vinyl)-cyclopropyl]-methanesulfonamide

(+)-E-Tetrahydro-furan-3-carboxylic acid(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide

E-Morpholine-4-carboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide

N-[1-(2-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-ethyl)-cyclopropyl]-methanesulfonamide

(+)-E-Tetrahydro-furan-2-carboxylic acid(3-{4-[3-chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-amide

(+)-Ethanesulfonic acid(1-methyl-3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide

(+)-Pyridine-2-carboxylic acid(1-methyl-3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide

and the pharmaceutically acceptable salts, solvates and prodrugs of theforegoing compounds.

1. A compound of the formula 1

or a pharmaceutically acceptable salt or prodrug thereof, wherein: m isan integer from 0 to 3; p is an integer from 0 to 4; each R¹ and R² isindependently selected from H and C₁-C₆ alkyl; R³ is selected from

wherein the foregoing R³ groups are optionally substituted by 1 to 3 R⁸groups; R⁴ is —(CR¹⁶R¹⁷)_(m)—C≡C(CR¹⁶R¹⁷)_(k)R¹³, or—(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(k)R¹³, wherein each k is an integer from 1to 3, and each m is an integer from 0 to 3; each R⁵ is independentlyselected from halo, hydroxy, —NR¹R², C₁-C₆ alkyl, trifluoromethyl, C₁-C₆alkoxy, trifluoromethoxy, —NR⁶C(O)R¹, —C(O)NR⁶R⁷, —SO₂NR⁶R⁷,—NR⁶C(O)NR⁷R¹, and —NR⁶C(O)OR⁷; each R⁶, R^(6a) and R⁷ is independentlyselected from H, C₁-C₆ alkyl, —(CR¹R²)_(t)(C₆-C₁₀ aryl), and—(CR¹R²)_(l)(4 to 10 membered heterocyclic), wherein t is an integerfrom 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group areoptionally substituted with an oxo (═O) moiety, the alkyl, aryl andheterocyclic moieties of the foregoing R⁶ and R⁷ groups are optionallysubstituted with 1 to 3 substituents independently selected from halo,cyano, nitro, —NR¹R², trifluoromethyl, trifluoromethoxy, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, hydroxy, and C₁-C₆ alkoxy; or R⁶ and R⁷,or R^(6a) and R⁷, when attached to the same nitrogen atom, can be takentogether to form a 4 to 10 membered heterocyclic ring which may include1 to 3 additional hetero moieties, in addition to the nitrogen to whichsaid R⁶, R^(6a), and R⁷ are attached, selected from N, N(R¹), O, and S,provided two O atoms, two S atoms or an O and S atom are not attacheddirectly to each other; each R⁸ is independently selected from oxo (═O),halo cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy,C₁-C₆ alkoxy, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —C(O)R⁶,—C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷, —NR⁶SO₂NR⁷R¹, —NR⁶C(O)NR¹R⁷,—NR⁶C(O)OR⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, —SO₂NR⁶R⁷, —S(O)_(j)(C₁-C₆alkyl) wherein j is an integer from 0 to 2, —(CR¹R²)_(t)(C₆-C₁₀ aryl),—(CR¹R²)_(t)(4 to 10 membered heterocyclic),—(CR¹R²)_(q)C(O)(CR¹R²)_(t)(C₆-C₁₀ aryl), —(CR¹R²)_(q)C(O)(CR¹R²)_(t)(4to 10 membered heterocyclic), —(CR¹R²)_(t)O(CR¹R²)_(q)(C₆-C₁₀ aryl),—(CR¹R²)_(t)O(CR¹R²)_(q)(4 to 10 membered heterocyclic),—(CR¹R²)_(q)S(O)_(j)(CR¹R²)_(t)(C₆-C₁₀ aryl), and—(CR¹R²)_(q)S(O)_(j)(CR¹R²)_(t)(4 to 10 membered heterocyclic), whereinj is 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R⁸groups are optionally substituted with an oxo (═O) moiety, and thealkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoingR⁸ groups are optionally substituted with 1 to 3 substituentsindependently selected from halo, cyano, nitro, trifluoromethyl,trifluoromethoxy, azido, —OR⁶, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —NR⁶C(O)R⁷,—C(O)NR⁶R⁷, —NR⁶R⁷, —NR⁶OR⁷, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—(CR¹R²)_(t)(C₆-C₁₀ aryl), and —(CR¹R²)_(t)(4 to 10 memberedheterocyclic), wherein t is an integer from 0 to 5; each R¹¹ isindependently selected from the substituents provided in the definitionof R⁸, except R¹¹ is not oxo(═O); R¹² is R⁶, —OR⁶, —OC(O)R⁶,—OC(O)NR⁶R⁷, —OCO₂R⁶, —S(O)_(j)R⁶, —S(O)_(j)NR⁶R⁷, —NR⁶R⁷, —NR⁶C(O)R⁷,—NR⁶SO₂R⁷, —NR⁶C(O)NR^(6a)R⁷, —NR⁶SO₂NR^(6a)R⁷, —NR⁶CO₂R⁷, CN, —C(O)R⁶,or halo, wherein j is an integer from 0 to 2; R¹³ is —NR¹R¹⁴ or —OR¹⁴;R¹⁴ is H, R¹⁵, —C(O)R¹⁵, —SO₂R¹⁵, —C(O)NR¹⁵R⁷, —SO₂NR¹⁵R⁷, or —CO₂R¹⁵;R¹⁵ is R¹⁸, —(CR¹R²)_(t)(C₆-C₁₀ aryl), —(CR¹R²)_(t)(4 to 10 memberedheterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbonatoms of the heterocyclic group are optionally substituted with an oxo(═O) moiety, and the aryl and heterocyclic moieties of the foregoing R¹⁵groups are optionally substituted with 1 to 3 R⁸ substituents; each R¹⁶and R¹⁷ is independently selected from H, C₁-C₆ alkyl, and —CH₂OH, orR¹⁶ and R¹⁷ are taken together as —CH₂CH₂— or —CH₂CH₂CH₂—; R¹⁸ is C₁-C₆alkyl wherein each carbon not bound to a N or O atom, or to S(O)_(j),wherein j is an integer from 0 to 2, is optionally substituted with R¹²;and wherein any of the above-mentioned substituents comprising a CH₃(methyl), CH₂ (methylene), or CH (methine) group, which is not attachedto a halogeno, SO or SO₂ group or to a N, O or S atom, is optionallysubsituted with a group selected from hydroxy, halo, C₁-C₄ alkyl, C₁-C₄alkoxy and —NR¹R².
 2. A compound according to claim 1 wherein R³ ispyridin-3-yl optionally substituted by 1 to 3 R⁸ groups.
 3. A compoundaccording to claim 1 wherein the following structural portion of thecompound of formula 1

is selected from the group consisting of3-Methyl-4-(pyridin-2-yloxy)-phenylamino3-Chloro-4-(pyridin-2-yloxy)-phenylamino3-Methoxy-4-(pyridin-2-yloxy)-phenylamino4-(pyridin-2-yloxy)-phenylamino 2-Methyl-4-(pyridin-2-yloxy)-phenylamino2-Methoxy-4-(pyridin-2-yloxy)-phenylamine3-Chloro-4-(6-methyl-pyridin-2-yloxy)-phenylamino3-Methoxy-4-(6-methyl-pyridin-2-yloxy)-phenylamino3-Methyl-4-(6-methyl-pyridin-2-yloxy)-phenylamino2-Methoxy4-(6-methyl-pyridin-2-yloxy)-phenylamino2-Methyl-4-(6-methyl-pyridin-2-yloxy)-phenylamino4-(6-methyl-pyridin-2-yloxy)-phenylamino3-Methoxy-4-(2-methyl-pyridin-3-yloxy)-phenylamino3-Methyl-4-(2-methyl-pyridin-3-yloxy)-phenylamino3-Chloro-4-(2-methyl-pyridin-3-yloxy)-phenylamino2-Methoxy-4-(2-methyl-pyridin-3-yloxy)-phenylamino2-Methyl-4-(2-methyl-pyridin-3-yloxy)-phenylamino4-(2-methyl-pyridin-3-yloxy)-phenylamino3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino3-Methoxy-4-(6-methyl-pyridin-3-yloxy)-phenylamino2-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino2-Methoxy-4-(6-methyl-pyridin-3-yloxy)-phenylamino4-(6-methyl-pyridin-3-yloxy)-phenylamino3-Methyl-4-(pyridin-3-yloxy)-phenylamino3-Chloro-4-(pyridin-3-yloxy)-phenylamino3-Methoxy-4-(pyridin-3-yloxy)-phenylamino2-Methyl-4-(pyridin-3-yloxy)-phenylamino2-Methoxy-4-(pyridin-3-yloxy)-phenylamino4-(pyridin-3-yloxy)-phenylamino3-Methyl-4-(2-methyl-pyrimidin-5-yloxy)-phenylamino3-Chloro-4-(2-methyl-pyrimidin-5-yloxy)-phenylamino3-Methoxy-4-(2-methyl-pyrimidin-5-yloxy)-phenylanino2-Methyl-4-(2-methyl-pyrimidin-5-yloxy)-phenylamino2-Methoxy-4-(2-methyl-pyrimidin-5-yloxy)-phenylamino4-(2-methyl-pyrimidin-5-yloxy)-phenylamino3-Methyl-4-(4-methyl-pyrimidin-5-yloxy)-phenylamino3-Chloro-4-(4-methyl-pyrimidin-5-yloxy)-phenylamino3-Methoxy-4-(4-methyl-pyrimidin-5-yloxy)-phenylamino2-Methyl-4-(4-methyl-pyrimidin-5-yloxy)-phenylamino2-Methoxy-4-(4-methyl-pyrimidin-5-yloxy)-phenylamino4-(4-methyl-pyrimidin-5-yloxy)-phenylamino3-Methyl-4-(2-methyl-pyridin-4-yloxy)-phenylamino3-Chloro-4-(2-methyl-pyridin-4-yloxy)-phenylamino3-Methoxy-4-(2-methyl-pyridin4-yloxy)-phenylamino2-Methyl-4-(2-methyl-pyridin-4-yloxy)-phenylamino2-Methoxy-4-(2-methyl-pyridin-4-yloxy)-phenylamino4-(2-methyl-pyridin-4-yloxy)-phenylamino3-Methyl-4-pyridin-4-yloxy)-phenylamino3-Chloro-4-(pyridin-4-yloxy)-phenylamino3-Methoxy-4-(pyridin-4-yloxy)-phenylamino2-Methyl-4-(pyridin-4-yloxy)-phenylamino2-Methoxy-4-(pyridin-4-yloxy)-phenylamino4-(pyridin-4-yloxy)-phenylamino3-Methyl-4-(2-methyl-pyrimidin-4-yloxy)-phenylamino3-Methoxy-4-(2-methyl-pyrimidin-4-yloxy)-phenylamino3-Chloro-4-(2-methyl-pyrimidin-4-yloxy)-phenylamino2-Methyl-4-(2-methyl-pyrimidin-4-yloxy)-phenylamino2-Methoxy-4-(2-methyl-pyrimidin-4-yloxy)-phenylamino4-(2-methyl-pyrrmidin-4-yloxy)-phenylamino3-Methyl-4-(6-methyl-pyrimidin-4-yloxy)-phenylamino3-Methoxy-4-(6-methyl-pyrimidin-4-yloxy)-phenylamino3-Chloro-4-(6-methyl-pyrimidin-4-yloxy)-phenylamino2-Methyl-4-(6-methyl-pyrimidin-4-yloxy)-phenylamino2-Methoxy-4-(6-methyl-pyrimidin-4-yloxy)-phenylamino4-(6-methyl-pyrimidin-4-yloxy)-phenylamino3-Methyl-4-(pyridazin-3-yloxy)-phenylamino3-Chloro-4-(pyridazin-3-yloxy)-phenylamino3-Methoxy-4-(pyridazin-3-yloxy)-phenylamino2-Methyl-4-(pyridazin-3-yloxy)-phenylamino2-Methoxy-4-(pyridazin-3-yloxy)-phenylamino4-(pyridazin-3-yloxy)-phenylamino3-Methyl-4-(6-methyl-pyridazin-3-yloxy)-phenylamino3-Chloro-4-(6-methyl-pyridazin-3-yloxy)-phenylamino3-Methoxy-4-(6-methyl-pyridazin-3-yloxy)-phenylamino2-Methyl-4-(6-methyl-pyridazin-3-yloxy)-phenylamino2-Methoxy-4-(6-methyl-pyridazin-3-yloxy)-phenylamino4-(6-methyl-pyridazin-3-yloxy)-phenylamino3-Methyl-4-(6-methyl-pyridazin-4-yloxy)-phenylamino3-Chloro-4-(6-methyl-pyridazin-4-yloxy)-phenylamino3-Methoxy-4-(6-methyl-pyridazin-4-yloxy)-phenylamino3-Methyl-4-(6-methyl-pyridazin-4-yloxy)-phenylamino2-Methoxy-4-(6-methyl-pyridazin-4-yloxy)-phenylamino4-(6-methyl-pyridazin-4-yloxy)-phenylamino3-Methyl-4-(3-methyl-pyridazin-4-yloxy)-phenylamino3-Chloro-4-(3-methyl-pyridazin-4-yloxy)-phenylamino3-Methoxy-4-(3-methyl-pyridazin-4-yloxy)-phenylamino2-Methyl-4-(3-methyl-pyridazin-4-yloxy)-phenylamino2-Methoxy-4-(3-methyl-pyridazin-4-yloxy)-phenylamino4-(3-methyl-pyridazin-4-yloxy)-phenylamino3-Methyl-4-(pyridazin-4-yloxy)-phenylamino3-Chloro-4-(pyridazin-4-yloxy)-phenylamino3-Methoxy-4-(pyridazin-4-yloxy)-phenylamino2-Methyl-4-(pyridazin-4-yloxy)-phenylamino2-Methoxy-4-(pyridazin-4-yloxy)-phenylamino4-(pyridazin-4-yloxy)-phenylamino3-Chloro-4-(1-methyl-1H-pyrazol-4-yloxy)-phenylamino3-Methoxy-4-(1-methyl-1H-pyrazol-4-yloxy)-phenylamino 3-Methyl-4-(1-methyl-1H-pyrazol-4-yloxy)-phenylamino2-Methoxy-4-(1-methyl-1H-pyrazol-4-ylaxy)-phenylamino2-Methyl-4-(1-methyl-1H-pyrazol-4-yloxy)-phenylamino, and4-(1-methyl-1H-pyrazol-4-ylaxy)-phenylamino.
 4. A compound according toclaim 1 wherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C≡C—(CR¹⁶R¹⁷)_(k)R¹³, wherein k isan integer from 1 to 3 and m is an integer from 0 to
 3. 5. A compoundaccording to claim 1 wherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C≡C—(CR¹⁶R¹⁷)_(k)R¹³,wherein k is an integer from 1 to 3 and m is an integer from 0 to 3,wherein R¹³ is —NR¹R¹⁴, wherein R¹⁴ is selected from —C(O)R¹⁵, —SO₂R¹⁵,and —C(O)NR¹⁵R⁷.
 6. A compound according to claim 1 wherein R⁴ is—(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(k)R¹³, wherein k is an integer from 1 to 3and m is an integer from 0 to
 3. 7. A compound according to claim 1wherein R⁴ is —(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(k)R¹³, wherein k is aninteger from 1 to 3 and m is an integer from 0 to 3, wherein R¹³ is—NR¹R¹⁴, wherein R¹⁴ is selected from —C(O)R¹⁵, —SO₂R¹⁵, and—C(O)NR¹⁵R⁷.
 8. A compound according to claim 1 wherein R⁴ is—(CR¹⁶R¹⁷)_(m)—C≡C—(CR¹⁶R¹⁷)_(k)R¹³ or—(CR¹⁶R¹⁷)_(m)—C═C—(CR¹⁶R¹⁷)_(k)R¹³, wherein k is an integer from 1 to 3and m is an integer from 0 to 3, R¹³ is —NR¹R¹⁴ or —OR¹⁴, R¹⁴ is R¹⁵,R¹⁵ is R¹⁸, and R¹⁸ is C₁-C₆ alkyl optionally substituted by —OR⁶,—S(O)_(j)R⁶, —NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶SO₂R⁷, —NR⁶CO₂R⁷, CN, —C(O)R⁶, orhalo.
 9. A compound according to claim 1 selected from the groupconsisting of:2-Methoxy-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide2-Methoxy-N-(3-{4-[3-methyl-4-(2-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide2-Fluoro-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinolin-6-yl}-prop-2-ynyl)-acetamide;E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide;[3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;2-Methoxy-N-(1-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-ylethynyl}-cyclopropyl)-acetamide;E-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-2-methoxy-acetamide;N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide;N-(3-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide;E-N-(3-{4-[3-Chloro-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide;E-2-Ethoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide;1-Ethyl-3-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-urea;Piperazine-1-carboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide;(±)-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide;2-Dimethylamino-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide;E-N-(3-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-methanesulfonamide;Isoxazole-5-carboxylic acid(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-amide;1-(1,1-Dimethyl-3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-3-ethyl-urea;and the pharmaceutically acceptable salts, prodrugs and solvates of theforegoing compounds.
 10. A pharmaceutical composition for the treatmentof abnormal cell growth in a mammal comprising an amount of a compoundof claim 1 that is effective in treating abnormal cell growth, and apharmaceutically acceptable carrier.